Annual Reports in Medicinal Chemistry, Volume 21

ANNUAL REPORTS IN MEDICINAL CHEMISTRY

Volume 21

Academic Press Rapid Manuscript Reproduction

ANNUAL REPORTS IN MEDICINAL CHEMISTRY Volume 21 Sponsored by the Division of Medicinal Chemistry of the American Chemical Society Editor-in-Chief: DENIS M. BAILEY STERLING-WINTHROP RESEARCH INSTITUTE RENSSELAER, NEW YORK

SECTION EDITORS BARRIE HESP JAMES A. BRISTOL FRANK C. SCIAVOLINO ROBERT W. EGAN RICHARD C. ALLEN BEVERLY A. PAWSON

W

ACADEMIC PRESS, INC.

1986

Harcourt Brace Jovanovich. Publishers

ORLANDO SAN DlEGO NEW YORK AUSTIN BOSTON LONDON SYDNEY TOKYO TORONTO

COPYRIGHT 0 1986 BY ACADEMICPRESS,INC. ALL RIGHTS RESERVED. NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING. OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOU PERMISSION IN WRITING FROM THE PUBLISHER

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CONTRIBUTORS PREFACE

xi xiii

I. CNSAGENTS

Section Editor: Barrie Hesp, Stuart Pharmaceuticals, Division of ICI Americas, Wilmington, Delaware 1.

Atypical Antipsychotic Agents Fredric J. Vinick and Michael R. Kozlowski, Pfizer Central Research, Groton, Connecticut

1

2. Anxiolytics, Anticonvulsants and Sedative-Hypnotics Michael Williams and Naokata Yokoyama, Research Department, Pharmaceuticals Division, CIBA-GEIG Y Corporation, Summit, New Jersey

11

3. Analgesics, Opioids and Opioid Receptors Roger James, ICI Pharmaceuticals Division, Macclesfield, Cheshire, England

21

4. Cognitive Disorders Fred M. Hershenson, John G. Marriott, and Walter H. Moos, Warner-Lambert/Parke-Davis Pharmaceutical Research Division ,Ann Arbor, Michigan

31

5. Drugs Acting at Central 5-Hydroxytryptamine Receptors Derek N. Middlemiss, Continental Pharrna, Mont-Saint-Guibert, Belgium Marcel Hibert and John R. Fozard, Merrell Dow Research Institute, Strasbourg Center, Strasbourg Cedex, France

41

6. Formation and Degradation of Neuropeptides Jan van Nispen and Roger Pinder, Organon International, Oss, The Netherlands

51

V

Contents

vi

11. PHARMACODYNAMIC AGENTS

Section Editor: James A. Bristol, Warner-Lambert/Parke-Davis Pharmaceutical Research Division, Ann Arbor, Michigan

7. Antihypertensive Agents Ronald D. Smith and John R. Regan, Rorer Group Inc., Tuckahoe. New York

63

8. Pulmonary and Antiallergy Agents

73

John G. Gleason, Carl D. Perchonock, and Theodore J. Torphy, Smith Mine & French Laboratories, Swedeland, Pennsylvania 9.

Calcium Modulators E. Wehinger and R. Gross, BA YER AG, Wuppertal-Elbetfeld, Federal Republic of Germany

10. Class I and I11 Antiarrhythmic Drugs

85

95

Mitchell I. Steinberg, William B. Lacefieid, and David W. Robertson, Lilh Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 11. Pharmacological Approaches in Acute Stroke

109

Graham Johnson and Frank W. Marcoux, Warner-Lambert/Parke-DavisPharmaceutical Research Division, Ann Arbor, Michigan 111. CHEMOTHERAPEUTIC AGENTS

Section Editor: Frank C.Sciavolino, Pfizer Central Research, Groton, Connecticut 12. Antimicrobial Drugs-Clinical

119

13. &Lactam Antibiotics

131

Problems and Opportunities Thomas D. Gootz, Pfizer Central Research, Groton, Connecticut

George L. Dunn, Smith Kline & French Laboratories, Philadelphia, Pennsylvania 14. Quinolone Antibacterial Agents James B. Cornett and Mark P. Wentland, Sterling-Winthrop

139

Research Institute, Rensselaer, New York 15.

Developments in Microbial Products Screening L.J. Nisbet and J. W. Westley, Smith Kline & French Laboratories, Swedeland, Pennsylvania

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Contents

16. Oncological Aspects of Growth Factors

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159

David S. Salomon and Isabelle Perroteau, Laboratory of Tumor Immunology and Biology, Division of Cancer Biology and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

IV. METABOLIC DISEASES AND ENDOCRINE FUNCTION Section Editor: Beverly A. Pawson, Verona, New Jersey 17. Chemical Control of Fertility

169

Malcolm R. Bell, Frederick H. Batzold, and Richard C. Winneker, Sterling-Winthrop Research Institute, Rensselaer, New York 18. Chemical Control of Androgen Action Gary H. Rasmusson, Merck Sharp & Dohme Research

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Laboratories, Rahway, New Jersey 19. Approaches to Drug Intervention in Atherosclerotic Disease

189

Roger S. Newton and Brian R. Krause, Warner-Lambert/ Parke-Davis Pharmaceutical Research Division, Ann Arbor, Michigan 20. Therapeutic Approaches to Rheumatoid Arthritis and Other Autoimmune Diseases Michael C. Venuti, Institute of Bio-Organic Chemistry, Syntex Research, Palo Alto, California

V.

20 1

TOPICS IN BIOLOGY

Section Editor: Robert W. Egan, Schering-Plough, Schering Research, Bloomfield, New Jersey 21. Special Topic: The Receptor: From Concept to Function

21 1

Michael Williams, Research Department, Pharmaceuticals Division, CIBA-GEIG Y Corporation, Summit, New Jersey S.J. Enna, Departments of Pharmacology and Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas 22.

Mitogenic Factors as Oncogene Products Harry N. Antoniades and Panayotis Pantazis, The Center for Blood Research and Harvard School of Public Health, Boston, Massachusetts

237

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Contents

23. Nucleotide Metabolism in Parasitic Protozoa Donald J. Hupe, Department of Biochemistry, Merck Institute for Therapeutic Research, Rah way, New Jersey 24. DNA Topoisomerases as Therapeutic Targets in Cancer Chemotherapy Grace L. Chen and Leroy F. Liu, Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland

247

257

25. Colony Stimulating Factors Dov Zbori, The Weizmann Institute of Science, Rehovot, Israel J. Allan Waitz, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California

263

26. Atrial Natriuretic Factor Rodney W. Lappe and Robert L. Wendt, Department of Experimental Therapeutics, Wyeth Laboratories, Inc., Philadelphia, Pennsylvania

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VI. TOPICS IN CHEMISTRY AND DRUG DESIGN Section Editor: Richard C. Allen, Hoechst-Roussel Pharmaceuticals, Inc., Somerville, New Jersey 27. Bioisosterism in Drug Design Christopher A. Lipinski, Pfizer Central Research, Groton, Connecticut 28. X-Ray Crystallography of Drug Molecule-Macromolecule Interactions as an Aid to Drug Design John J. Stezowski and Krishnamoorthy Chandrasekhar, Institut f u r Organische Chemie Biochemie und Isotopenforschung der Universitat Stuttgart, Stuttgart, Federal Republic of Germany 29. Recent Developments in Computer-Assisted Organic Synthesis Nicholas J . Hrib, Hoechst-Roussel Pharmaceuticals, Inc. , Somerville, New Jersey 30. Tandem Mass Spectrometry for the Identification of Drug Metabolites Mike S. Lee and Richard A. Yost, Department of Chemistry, University of Florida, Gainesville, Florida Robert J. Perchalski, Pharmatec, Inc., Alachua, Florida

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VII. WORLDWIDE MARKET INTRODUCTIONS Section Editor: Richard C. Allen, Hoechst-Roussel Pharmaceuticals, Inc., Somerville, New Jersey 31. To Market, to Market-1985 Richard C.Allen, Hoechst-Roussel Pharmaceuticals, Inc., Somerville, New Jersey

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COMPOUND NAME AND CODE NUMBER INDEX CUMULATIVE CHAPTER TITLES KEYWORD INDEX, VOLUMES 1-21 CUMULATIVE CONTRIBUTOR INDEX, VOLUMES 1-21

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Allen. Richard C . . . . . . . . . . . . . . . . Antoniades. Harry N ............. Batzold. Frederick H ............. Bell. Malcolm R ................. Chandrasekhar. Krishnamoorthy . . Chen. Grace L . . . . . . . . . . . . . . . . . . Cornett. James B................ Dunn. George L . . . . . . . . . . . . . . . . . Enna. S.J ....................... Fozard. John R .................. Gleason. John G ................. Gootz. Thomas D ................ Gross. R ....................... Hershenson. Fred M ............. Hibert. Marcel .................. Hrib. Nicholas J ................. Hupe. Donald J ................. James. Roger ................... Johnson. Graham ............... Kozlowski. Michael R. . . . . . . . . . . . Krause. Brian R ................. Lacefield. William B. . . . . . . . . . . . . Lappe. Rodney W . . . . . . . . . . . . . . . Lee. Mike S ..................... Lipinski. Christopher A . . . . . . . . . . Liu. Leroy F.................... Marcoux. Frank W . . . . . . . . . . . . . . Marriott John G . . . . . . . . . . . . . . . . Middlemiss. Derek N .............

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Moos. Walter H . . . . . . . . . . . . . . . . . Newton. Roger S................ Nisbet. L.J. .................... Pantazis. Panayotis .............. Perchalski. Robert J ............. Perchonock. Carl D .............. Perroteau. Isabelle .............. Pinder. Roger. .................. Rasmusson. Gary H .............. Regan. John R . . . . . . . . . . . . . . . . . . Robertson. David W . . . . . . . . . . . . . Saloman. David S................ Smith. Ronald D . . . . . . . . . . . . . . . . Steinberg. Mitchell I ............. Stezowski. John J ................ Torphy. Theodore J .............. van Nispen. Jan ................. Venuti. Michael C . . . . . . . . . . . . . . . Vinick. Fredric J ................. Waitz. J . Allan .................. Wehinger. E .................... Wendt. Robert L . . . . . . . . . . . . . . . . Wentland. Mark P ............... Westley. J.W. .................. Williams. Michael ............ 11 Winneker. Richard C............. Yokoyama. Naokata ............. Yost Richard A . . . . . . . . . . . . . . . . . Zipori. Dov ....................

323 237 169 169 293 257 139 13 1 211 41 73 119 85 31 41 303 247 21 109 1 189 95 273 313 283 257 109 31 41

31 189 149 237 313 73 159 51 179 63 95 159 63 95 293 73 51 201 1 263 85 273 139 149 211 169 11 313 263

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Volume 21 of Annual Reports in Medicinal Chernktry contains 31 chapters in seven sections: CNS Agents, Pharmacodynamic Agents, Chemotherapeutic Agents, Metabolic Diseases and Endocrine Function, Topics in Biology, Topics in Chemistry and Drug Design, and Worldwide Market Introductions. The last of these sections, first introduced in Volume 19, continues to be a popular adjunct to the more classic topics of this serial. In this volume, the Section Editors have been granted latitude in addressing the process and future of drug discovery, as well as the more traditional reporting of the last year’s events. Thus, in each section there appear chapters that attempt to add the perspective of future opportunity to the established accomplishments of the past and present. These chapters include potential mechanistic approaches to the discovery of safer neuroleptics (chapter l), and agents for the treatment of acute ischemic stroke (chapter ll), atherosclerosis (chapter 19), and autoimmune diseases (chapter 20). Issues confronting discovery research in the maturing antibiotic area are addressed in chapter 12. In Section VI, the utility of powerful tools to probe molecular interactions (chapter 28) and structure (chapter 30) is described. Because of their scientific importance and rapidly evolving therapeutic potential, various aspects of molecular biology have been covered in several chapters. In some instances these general chapters extend across therapeutic areas. For example, chapters 16 and 22 discuss the oncogenic potential of peptide growth factors, the former from a more medical viewpoint and the latter from a biochemical perspective. Updated in this volume are the areas of anxiolytics, anticonvulsants, sedative-hypnotics, analgesics, antihypertensives, pulmonary, antiarrhythmic and antiallergy agents, and antiinfectives. In addition, the potential medical utilities of atrial natriuretic factor and colony stimulating factors are reviewed. The current status of bioisosterism in drug design and the use of computers in planning organic syntheses are discussed in Section V1. In its continuing effort to vitalize the format of Annual Reports, the editorial board has elected to experiment with the addition of an in-depth review of an area globally important to drug discovery. In this year’s volume the concept and function of receptors are extensively covered in the section on Topics in Biology (chapter 21). It has been a pleasure to work with the Section Editors and contributors to this volume. They have, indeed, generated and assembled a fine collection of reports. As usual, this volume could not have been completed without the assistance of Martha Johnson, to whom I am most grateful. Denis M. Bailey RensseIaer, New York May 1986

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Section I

- CNS Agents

Editor: Barrie Hesp, Stuart Pharmaceuticals Division of ICI Americas, Wilmington, DE 19897

Chapter 1. Atypical Antipsychotic Agents

Fredric J. Vinick and Michael R. Kozlowski Pfizer Central Research, Groton, CT 06340 Introduction and Background -While neuroleptic drugs continue to represent the best form of treatment for schizophrenia, they still possess two major weaknesses. First, as many as one-third of the patients suffering from this disorder, particularly those with a preponderance of negative symptoms, do not respond to neuroleptic treatment.1.2 Second, all neuroleptics currently approved in the United States produce extrapyramidal side effects (EPS).' The most common forms of EPS are Parkinsonism, dystonia, akathisia and tardive dyskinesia (TD). The first three types occur early in the course of neuroleptic treatment and can usually be ameliorated. The fourth form, TD, develops only after months or years of therapy. It can be life-threatening and is very difficult to reverse even after termination of neuroleptic treatment.3 Both acute and chronic EPS are believed to result from blockade of dopamine (DA) receptors in the neostriatum of the brain.2~3The acute symptoms are likely due to a decrease in striatal DA functioning. On the other hand, TD appears to result from the ability of the striatal DA system to overcome the neuroleptic blockade and ultimately reestablish more normal levels of neurotransmission. Since the striatal DA receptors have been made supersensitive by chronic blockade, the restored dopaminergic stimulation produces the abnormal movements of TD.3 In recent years efforts have been focused on the need for drugs with greater clinical efficacy, and/or reduced liability to produce EPS, especially TD. Drugs which possess this clinical profile, or are predicted to exhibit it based on preclinical data or mechanistic hypotheses, have been termed "atypical antipsychotics." Putative Mechanisms Subserving Atypical Activity - The pharmacological mechanisms most often suggested as contributing to atypical antipsychotic activity (sometimes in combination) are described in this section. Selective antagonism of limbic DA receptors -The consensus is that antipsychotic drugs ameliorate psychosis by blocking the DA receptors in limbic regions of the brain (e.g., nucleus accumbens, olfactory tubercle, frontal cortex) while EPS result from the concomitant blockade of DA receptors in the striatum.4~5It follows that a drug which preferentially blocks limbic DA receptors might have a lower propensity to produce EPS.6 Behavioraltests are generally used to identify DA antagonists which are selective for the limbic system. Inhibition of the enhanced locomotor behavior resulting from the administration of dopamine agonists is thought to result from limbic (i.e., nucleus accumbens) DA receptor blockade, while reversal of the stereotyped behavior produced by higher doses of DA agonists appears more related to the inhibition of striatal DA receptors.7-9 Likewise, the blockade of striatal DA receptors seems important in mediating catalepsy.10-12 Therefore, limbic DA receptor blockade, and presumably antipsychotic activity, would be indicated by the inhibition of locomotor activity, while decreased striatal DA receptor blockade, and reduced EPS liability, would be predicted by little or no inhibition of stereotypy, and the absence of catalepsy. The absence of supersensitivity to DA agonists in behavioral paradigms subserved by striatal mechanisms, following chronic administration of a putative antipsychotic, may be indicative of reduced TD liability; the ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21

Copyright 0 1986 by Academic Press, Inc. All rights of reproduction in any form reserved.

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neurochemical correlate of such behavioral measures is the absence of striatal DA receptor proliferation.3

-

Blockade of muscarinic receptors in the striatum produces AnNmuscarinic Activity behavioral effects opposite to those caused by blockade of DA receptors. Thus, antimuscarinic drugs, such as scopolamine, potentiate the stereotypy induced by amphetamine, while atropine reverses haloperidol-induced catalepsy.8.13 The antimuscarinic potencies of antipsychotic drugs are inversely correlated with their liabilities to produce EPS in man.14915 This supports the hypothesis that concomitant antimuscarinic activity will attenuate the effects of DA antagonists in the striatum. Gamma-Arninobutyricacid (GABA) agonist activity - Chronic administration of neuroleptics causes many changes in brain GABAergic systems, including a decrease of GABA turnover in limbic and striatal regions, decreased activity of glutamic acid decarboxylase (GAD) in the substantia nigra and a proliferation of nigral GABA receptors. 18-18 These changes in the GABAergic system could contribute to TD in two ways. First, since the GABAergic striatonigral pathway affects neurotransmission from the striatum to other brain regions, a proliferation of nigral GABA receptors could facilitate the passage of information down this pathway, thereby enhancing the effects of striatal DA receptor activation and (ultimately) inducing TD.19 Conversely, the decrease in nigral GAD levels and GABA turnover could itself lead to TD.20 It has been suggested that the combination of a GABA agonist with a dopamine antagonist could prevent these processes, either by preventing nigral GABA receptor proliferation or by maintaining tonic GABAergic activation, and that such a combination would have a reduced TD liability.1@~~ However, since GABA agonists do not improve psychosis (and may even worsen it), drugs with this profile would not be expected to have increased clinical efficacy.21'22 Noradrenergic antagonist activity - Norepinephrine(NE)-containing brain systems have also been implicated in the etiology of schizophrenia. Schizophrenic patients, particularlythose with the chronic form of the disease, have elevated levels of NE and its major metabolite, 3-methoxy-4-hydroxyphenylglycol(MHPG), in some brain areas as well as elevated NE levels in their cerebrospinal fluid.23-25 These results point to altered noradrenergic system functioning in schizophrenia, interpreted as increased activity by sorne,23*28 and decreased activity by others.24~25Altered noradrenergic function might contribute directly to psychosis or the effects could be indirect via modulation of the DA system. The latter possibility is supported by experimental data showing an interaction of noradrenergic and dopaminergic systems in a number of behaviors including amphetamine-induced hyperactivity, amphetamine-induced stereotypy, conditioned avoidance, aggression, feeding, motor activity and catalepsy.27-30 Support for a beneficial effect of NE system antagonism in schizophrenia has also come from clinical trials of propranolol in this disorder. Most studies have shown benefit with propranolol alone or in combination with a neuroIeptic,31-37 although some have failed to demonstrate eff icacy.38-40

serotonin (5-HT)entagonist activity -5-HT antagonists can reverse some of the biochemical and behavioral effects of neuroleptics. Thus, neuroleptic-induced catalepsy is prevented or reduced by 5-HT receptor antagonists (cyproheptadine, mianserin, or methysergide), or by lesions of the serotonergic system.41-44 In addition, methysergide, mianserin and cinanserin block the increase in DA turnover produced by haloperidol in the striatum.6 Cyproheptadine and methysergide also reverse fluphenazine's inhibitory effect on the locomotor behavior produced by direct administration of DA in the nucleus accumbens: on this basis, it is unlikely that 5-HT antagonists would improve antipsychotic efficacy,* although serotonergic overactivity has been associated with some syndromes of schizophrenia.47 Other mechanisms - A drug which does not directly block DA receptors, but produces some of the electrophysiological, biochemical or behavioral effects common to clinically active neuroleptics, might possess antipsychotic activity without the risk of EPS. The behavioral tests usually employed to search for this activity, such as conditioned avoidance behavior, intracranial self-stimulation and unconditioned behaviors, are independent of a priori DA receptor blockade.@ However, some investigators have also employed DA-induced behaviors including the climb-

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3

ing and aggressive behaviors induced by ap0morphine.~8Several neuropeptides, including cholecystokinin (CCK), neurotensin and des-tyrosine-gamma-endorphin(DTGE) produce effects on DA turnover or behavior that simulate those of neuroleptics without binding directly to DA receptor sites.49-55 However, clinical trials of DTGE have shown only modest, short-lived antipsychotic activity, while trials of CCK have failed to demonstrate activity reproducibly.56-58 Recent studies have described a putative endogenous peptide which binds to the sigma opiate receptor.= Since agonists which bind to this receptor typically have potent psychotogenic activity (e.g., phencyclidine, PCP),GO it is thought that an antagonist might possess antipsychotic efficacy.61 Again, blockade of DA receptors would be circumvented. Clozaplne: The Prototypical Atypical - The clinical effectiveness of clozapine has been documented in a large number of studies which, almost without exception, have noted the virtual absence of EPS.62-67Furthermore, clozapine has often been rated as more efficacious than classical agents such as chlorpromazine.68-75 The extensive efforts to elucidate the mechanisms underlying clozapine’s unique and desirable clinical profile can be analyzed with regard to the six putative rationales for atypical activity set forth in the previous section. Selective antagonism of limbic DA receptors - Selective activity in limbic systems has been noted in the behavioral, biochemical, neurochemicaland electrophysiologicaleffects of clozapine. In behavioral tests, clozapine inhibits the locomotor stimulation but not the stereotypy induced by apomorphine, and does not produce catalepsy.76.77 Biochemically, clozapine produces a greater enhancement of DA turnover (at least with optimal treatment parameters) in limbic than striatal brain regions, while conventional neuroleptics produce an equal or greater effect in the striatum.78-82 Likewise, while classical drugs (with the exception of thioridazine) acutely produce an increase, and chronically a decrease, in the firing rates of DA-containing neurons projecting to both limbic and striatal brain regions, clozapine produces these effects preferentially or exclusively in neurons projecting to the limbic region.83184 Furthermore, clozapine selectively binds to limbic compared to striatal brain regions, whereas conventional neuroleptics do not reproducibly show any preference or are striatally selective.85-87 However, selective binding may not occur in man.88 While the consensus is that clozapine does induce supersensitivity on chronic administration, this effect is believed to apply more to behaviors mediated by limbic, rather than striatal systems.m2 Also, in contrast to conventional neuroleptics, chronically administered clozapine does not cause a proliferation of striatal DA receptor binding sites.92193These data suggest that clozapine produces a weak striatal DA receptor blockade, and are consistent with the reported absence of TD in patients treated for extended periods of time with this drug. Antimuscarinic activity - Clozapine is an anticholinergic agent with high affinity for muscarinic cholinergic receptors.77 A study of the effect of clozapine (intra-accumbens administration) on amphetamine-induced stereotypy concluded that clozapine’s potent anticholinergic activity modulates its mesolimbic dopaminergic properties: the combination of clozapine with a cholinergic agonist effectively antagonized stereotypy, whereas clozapine in combination with an anticholinergic agent significantly potentiated the stereotyped behaviors.94 Muscarinic binding in the mouse brain (cortex, hippocampus, and striatum) is increased upon chronic administration of clozapine, consistent with its anticholinergic activity; this up-regulation of muscarinic sites may offer protection against TD.95 The anticholinergic effects of clozapine might also be responsible for its preferential elevation of DA turnover in limbic areas, since this effect can be mimicked by co-administrationof haloperidol and an anticholinergic drug.78 GABA agonist activily - Unlike haloperidol or chlorpromazine, clozapine does not upregulate GABA receptors in the substantia nigra following chronic administration. It has been speculated that the anticholinergic activity of clozapine interferes with the activation of nigrostriatal pathways required for the suppression of GABA transmission, thus preventing the development of supersensitive GABA receptors “downstream” from dopamine receptors.” However, clozapine may exert a more direct effect on GABA receptors since it has been found to facilitate the binding of 3H-flunitrazepam to mouse brain in vivo (an effect produced by GABA agonists).96

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Noradrenergic antagonist activity - Chronic administration of haloperidol to rats was shown to inactivate both A9 (striatal) and A10 (limbic) neurons in an electrophysiological study, whereas clozapine under the same treatment protocol inactivated A10 cells selectively. Chronic coadministration of haloperidol and an alphal antagonist drug (prazosin) mimicked the chronic clozapine effect. The combination of haloperidol with an alpha?,antagonist did not produce clozapine-like A10 selectivity. Thus, alpha, antagonism may be responsible in part for some of clozapine’s selective limbic effects.97 5-HTantagonist activity - The 5-HT2antagonist properties of clozapine have been demonstrated by several investigators. In addition to inhibiting 5-HT2receptor binding, clozapine blocks the ability of rats to discriminate quipazine, a direct 5-HT receptor agonist.98 In another set of experiments clozapine blocked the potentiation of apomorphine-induced hypermotility by LSD in the rat,998100an effect whose locus of action appears to be the median raphe nucleus. Chronic administration of clozapine causes adaptive changes in the serotonin system: 5-HT2 receptors (frontal cortex) are down-regulated by 63% in the rat.101

Other mechanisms - 3H-Clozapine has been utilized in several binding experiments in efforts to determine whether this drug might label a novel, pharmacologically relevant site. Much of the binding was to muscarinic receptors, and the remaining specific binding was largely non-dopaminergic.1oz-104To date there is no conclusive evidence for a unique, functionally significant “clozapine binding site.” Clinically Tested Putative Atypical Agents - In addition to clozapine, a number of drugs from diverse structural classes have been reported to exhibit atypical clinical activity. The substituted benzamides(e.g., sulpiride) have not been included in this review for two reasons. First of all, controversy still exists as to whether sulpiride, the most well-studied agent from this structural class, truly displays atypical activity: it has been difficult to determine if, in fact, sulpiride, compared to classical neuroleptics, possesses roughly equivalent EPS liability when administered in doses high enough to be antipsychotic.105 Sulpiride is a relativelyweak antagonist at the D2 DA receptor but has no effect on NE, 5-HT, ACh, histamine, or GABA receptors.106-108 Chronic administration of high doses of sulpiride does produce behavioral and biochemical supersensitivity to DA agonists.109 Very high doses of this agent given acutely have been shown to induce catalepsy.87

Secondly, the newer benzamides are, like sulpiride, selective D2 blockers. Drugs such as etoclopride and raclopride differ from sulpiride primarily in terms of greater potency as DA antagonists.110.111 Since little or no clinical information regarding the potent benzamides is available at the present time, it will be best to review these drugs after a number of independent studies of efficacy and tolerance have been published.

Fluperlapine (1) - This drug was effective in several open and single blind trials and did not produce EPS.112-117 Like clozapine, its atypical activity could be due to any of a number of mechanisms.118 Fluperlapine may be a selective antagonist at limbic DA receptors since it is weak as a blocker of apomorphine stereotypy and does not induce catalepsy (both striatal effects). However, its activity against DA agonist-induced hyperlocomotion has apparently not been examined, so that no limbic versus striatal comparison of behavioral effects can be made. In receptor-bindingstudies fluperlapine shows weak affinity for the DA receptor but binds potently to muscarinic, 5-HT2and alpha,-adrenergic sites. While fluperlapine is anticholinergic in vivo, and increases striatal levels of the DA metabolite, homovanillic acid (HVA), it is much less effective at increasing levels of the norepinephrine metabolite, MHPG, in the brain system. Thus, some combination of antidopaminergic,antimuscarinicor antiserotonergicactivities may be responsible for the atypical psychotherapeutic profile of this drug. Rimcazole (2) - This agent has been tested in several open clinical trials where it has reportedly shown efficacy with minimal EPS.119-123The antipsychotic activity of rimcazole appears not to involve DA receptors directly: it is extremely weak as an inhibitor of D2 receptor binding.124 Rirncazole may act as a selective DA antagonist in the limbic system since it increases the concentrations of the DA metabolites, HVA and 3,4-dihydroxyphenylaceticacid (DOPAC), in the prefrontal cortex but not in the striatum.125 In addition, it does not block apomor-

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5

phine or amphetamine-inducedstereotypy, nor does it induce catalepsy.126 Rimcazole does block apomorphine-induced climbing in mice and inhibits several forms of aggressive behavior, but does not inhibit conditioned avoidance behavior.126 The only potent binding interaction of rirncazole is at the site labeled by 3H-SKF-10047.127 While this observation may suggest sigma receptor antagonism as a mechanism of action, rimcazole did not inhibit binding of the putative sigma receptor agonist and psychotogen, 3H-PCP.127 -NMe

1 Ritanserin(3)- This drug has shown clinical efficacy with reduced EPS liability in both open and controlled clinical trials (with or without an added neuroleptic).12B-130 Ritanserin is a very potent 5-HT2antagonist. By comparison, it is considerably weaker as a D2 receptor blocker. Despite its binding potency at DA receptor sites, ritanserin does not alter levels of DA or its metabolites, except at very high doses. It is also ineffective in antagonizing behaviors produced by dopaminergic stimulation. Ritanserin has moderately high potencies at alphaland alpha2-adrenergicbinding sites, which may contribute to its atypical profile.131 F

I

Setoperone (4) - This drug has been tested in open clinical trials in patients with mainly negative schizophrenic symptoms.132 It was efficacious in these studies with a reduced liability to produce EPS. Setoperone inhibits DA and 5-HT2 binding with approximately equal potencies, and blocks the in vivo effects of tryptamine, as well as those of amphetamine and apomorphine (including apornorphine-induced stereotypy).13*134 It is devoid of anticholinergic activity.‘% Other Putative Atypical Antipsychotics -This section will discuss those agents which have been purported to possess atypical antipsychotic activity based on preclinical biochemical, neurochemical or behavioral data. We have omitted from this review the selective D1DA antagonist, Sch 23390, which has been recently described elsewhere.135 A functional interrelationship between D1 and D2 receptors has been noted by several investigators.136~137Like conventional neuroleptics, Sch 23390 has been reported to induce catalepsy,l38 although there has been some disagreement as to whether the observed immobile state is a true haloperidollike catalepsy.135 Also, this drug has been found to potentiate haloperidol-induceddyskinesias in sensitized squirrel monkeys.139 Although Sch 23390 has been shown to differ from classical agents by virtue of a lack of direct effects on DPreceptors,140~141it is difficult to categorize this drug as atypical in the absence of clinical data. BMY-14802(5) -The putative atypical activity of this compound is based on its neurolepticlike effects in electrophysiological,biochemical and behavioral tests in the absence of in vitm DA receptor blockade. BMY-14802 lacks affinity for any binding sites thus far examined, including dopaminergic (D2), muscarinic, serotonergic or adrenergic (alphal- or beta-).14”1w However, it inhibits conditioned avoidance behavior, apomorphine-induced stereotypy and amfonelic acid-

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CNS Agents

Hesp, Ed.

induced locomotion, and does not produce catalepsy.142-144Also, like neuroleptics, it increases DA cell firing and DA turnover in the striatum when administered systemically.~4~

2 7

6 L l i M a CGS70746B (6) - This compound displays neuroleptic-activity without in vitro DA receptor blockade.145 It blocks neither D2nor muscarinic binding sites. However, CGS-107468 inhibits conditioned avoidance behavior and intracranial self-stimulation, and does not produce the acute dyskinetic syndrome in monkeys. Like other neuroleptics, it produces an increase in striatal levels of the DA metabolite, DOPAC; however, this increase is small. CGS-107468 also possesses weak alpha-adrenergic antagonist properties. 5

Cinuperone (7) - This agent selectively inhibits DA-dependent behaviors mediated by the limbic system.14@,147 Thus, cinuperone inhibits methamphetamine-induced locomotor behavior with higher potency than it blocks amphetamine-induced stereotypy, and does not induce catalepsy. In addition, this drug inhibits apomorphine-induced climbing, conditioned avoidance behavior, intra-cranial self stimulation and apomorphine-inducedturning in lesioned animals. Cinuperone is a potent inhibitor of DA (Dz) and NE (alphal), but not muscarinic binding.

-

Amperozide (8) This compound is selective for presynaptic DA terminals in the limbic system and is also a potent 5-HT antagonist.l@ In principle, attenuation of DA systems via presynaptic mechanisms could result in reduced EPS liability. However, although behavioral data suggest that amperozide acts selectively at presynaptic DA terminals, it apparently does not affect DA synthesis.149 Amperozide inhibits the locomotor behavior, but not the stereotypy caused by amphetamine, and does not cause catalepsy. These findings provide behavioral evidence for limbic selectivity.149~150The potent 5-HT2 receptor binding and decreased 5-HT cell firing produced by amperozide suggest functional antagonism of the serotonergic system.150 However, these antagonist properties may be partially mollified by the ability of this agent to inhibit 5-HT uptake.150 Amperozide also has weak effects on noradrenergic binding (alpha,and alpha2-), uptake and cell firing.150 DapipraZOre (9) - Dapiprazole is reported to be neuroleptic-like but devoid of direct DA receptor-blockingactivity. However, the claim for lack of DA receptor inhibition rests on the failure of this compound to inhibit apomorphine stereotypy or to induce catalepsy.151 These activities are also absent in some known DA receptor antagonists (e.g., clozapine). Dapiprazole does block amphetamine locomotor behavior, which indicates selectivity for the limbic system, and also inhibits conditioned avoidance behavior.151 It is a potent noradrenergic blocker (alpha-, but not beta-) and a somewhat less potent inhibitor of serotonin, but is devoid of anticholinergic activity.152

w

Me

9

HMe

Chap. 1

A t y p i c a l Antipsychotic Agents

Vinick, Koslowski

1

Mezilamine (70) - This agent is classified as an atypical antipsychotic on the basis of its selectivity for the limbic DA system and its weak induction of catalepsy.153~154Mezilamine inhibits DA (D2) binding in vitro (JH-haloperidol) more potently in the olfactory tubercle than in the striatum. It also increases DA turnover to a greater extent in the nucleus accumbens than in the striatum.153.154 However, some of these effects may be attributable to alphaadrenergic mechani~ms.153~154 Mezilamine does not inhibit muscarinic cholinergic binding and does not display GABA agonist activity in vivo.155 Like other neuroleptics, mezilamine blocks apomorphine-induced stereotypy and yawning, and conditioned avoidance behavior.155~156

MJ-73980-1 (77) - On the basis of its failure to produce catalepsy on acute administration, or striatal supersensitivity on chronic administration, it is predicted that this compound will show decreased EPS liability.157,158 MJ-13980 does, however, block apomorphine-induced stereotypy and striatal 3H-spiroperidol binding, which indicates inhibition of the striatal DA system.158 It is devoid of antimuscarinic activity.157

Tiasperone (72) -Tiasperone is weakly cataleptogenic and fails to induce striatal DA recep tor binding site proliferation on chronic administration; it does, however, inhibit conditioned avoidance behavior and arnfonelic acid-induced locomotor behavior.1BJm Tiasperone is more effective in preventing firing of DA-containingneurons which project to limbic than to striatal areas, following chronic administration.161The above effects are consistent with limbic selectivity. By contrast tiasperone is as potent an inhibitor of apomorphine-induced stereotypy (a striatally-mediatedbehavior) as of amfonelic acid-induced hyper locomotion.^^^^^^^ Receptorbinding studies show that 12 has high affinity for DA (Dd, adrenergic (alphal) and 5-HT receptors: it does not bind to muscarinic receptors.160

Summary - We have described many of the compounds under development which are claimed to be atypical antipsychotic drugs free from the major deficiencies of currently marketed agents. However, it will take many years of clinical studies before it can be determined, which, if any, of these are truly “atypical” antipsychotics, both from the standpoint of improved efficacy and reduced EPS liability. REFERENCES 1. T J. Crow, Trends Neumsci., 6. 351 (1982). 2. J. Davis, P. Janicak. R. Linden, J. Moloney and I, Pavkovic in “Neumleptics: Neurochemical, Eehevioral. and Clinical PerSPeCrives.“ J.T. Coyle and S.J. Enna. Eds.. Raven Press, New York, NY, 1983, p. 15. 3. R.J. Baldessarini and D. Tarsy. Ann. Rev. Neumsci., 3, 23 (1980). 4. N.-E. Anden, J. Psychlat. Res., 11. 97 (1974). 5. T.J. Crow, C. Med. J., 280, 66 (1980). 8. R.L. Borison and 8.1. Diamond, Brain Res. Bull., 11, 215 (1983). 7. D.M. Jackson. N.-E. Anden and A. Dahlstrom. Psychopharmacol., 45, 139 (1975). 8. 8. Costall. C.D. Marsden, R.J. Naylor and C.J. Pycock, Erain Res., 123, 89 (1977). 9. D.M. Staton and P.R. Solomon, Physiol. Psycho/.. 12, 159 (l9W). 10. 8. Costall and J.E. Olley, Neumpharmecol., 10, 297 (1971). 11. T. Honma and H. Fukushima. Jap. J. Phamecd.. 28. 231 (1978). 12. K.B. Koffer, S. Berney and 0. Hornykiewicz. Eur. J. Pharmacol., 47. 81 (1978). 13. T. Arnfred and A. Randrup, Acta Phamacol. Toxicd., 26, 384 (1968). 14. R.J. Miller and C.R. Hiley. Nature. 248. 598 (1974). 15. S.H. Snyder, D. Greenberg and H.I. Yamamura. J. Psych@. Res.. 11. 91 (1974). 16. C.C. Mao. D.L. Cheney. E. Marco. A. Revuelta and E. Costa. Brain Res., 132. 375 ( l e v . 17. K. Gale, Nature, 283. 589 (1980). 18. L.M. Gunne and J.-E. Haggstrom, Psychophermacol., 81. 191 (1983). 19. K. Gale and M. Casu, M o k . Cell, Eiochem., 39.389 (1981). 20. H.C. Fibiger and K.G. Lloyd, Trends Neunwci., 7, 482 (1984). 21. C.A. Taminga, J.W. Crayton and T.N. Chase, Am. J. Psychiet, 131, 746 (1978). 22. W.M. Glazer, D.C. Moore, M.B. Bowers, B.S. Bunney and M. Rolfman, Psychopharmacol., 87. 580 (1985).

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A t y p i c a l Antipsychotic Agents

V i n i c k , Koslowski

2

96. R.G. Browne and B.K. Koe, Psychopharmacol., 76, A5 (1982). 97. L.A. Chiodo and B.S. Bunney. J. Neurosci., 9, 2539 (1985). 98. R.L. Friedman, E. Sanders-Bush and R.L. Barrett, Eur. J. Pharmacol., 106, 191 (1985). 99. R. Morgenstern, H. Fink and W. Oelssner. Pharmacol. Biochem. and Behav., 18, 13 (1983). 100. H. Fink, R. Morgenslern and W. Oelssner. Phamacol. BMchem. andBehav.. 20, 513 (1984). 101. G.P. Reynolds, N.J. Garrett, N. Rupniak, P. Jenner and C.D. Marsden. Eur. J. Phmacol.. 89. 325 (1963). 102. T. dePaulis. C.R. Betts, H.E. Smith, P.L. Mobley, D.H. Manier and F. Sulser. J. Med. Cham., 24. 1021 (1981). 103. H.R. Burki, Life Sci, 26, 2187 (1980). 104. D. Hauser and A. Closse, Life Sci., 2 3 , 557 (1978). 105. J. Gerlach. K. Behnke, J. Hellberg, E. Muck-Andersen and H. Nielsen, 61.J. Psychiar,, 147, 263 (1985). 106. P. Boyer and P. Pichot in "Psychi8fry: The Stare of the An", Vol. 3. P. Pichot. P. Berner. R. Wolf and K. Thau. Eds.. Plenum Press, New York. 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Chapter 2. Anxiolytics, Anticonvulsants arid Sedative-Hypnotics Michael Williams and Naokata Yokoyama Research Department, Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, NJ 07901 Introduction - Public interest in anxiety has continued to increase, with over 13 million individuals in the U.S.A. being affected by this disorder,' At the preclinical level, the emphasis has been on attempts to separate the various pharmacological actions of the benzodiazepines (i.e. anxiolytic, sedative, anticonvulsant and muscle relaxant), into distinct processes mediated via different receptor subtypes, although Concurrently this approach is more molecular than physiological. based on the activity of buspirone (1)6 and related compounds (2)-(5),7-4 the mechanistic emphasis has switched to the role of serotonin in the

*-'

etiology of a n ~ i e t y . ~Compound 1 does not interact with central benzodiazepine (BZ) receptors, is devoid of sedative and muscle relaxant action8 and does not potentiate alcohol.6 There have been new developments pertaining to the putative endogenous ligand for the central receptor1' and the functional role of peripheral BZ receptors (PBZR) .11'12

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Benzodiazepine receptor ligands Compounds directly interacting with the central BZ receptor include the pyrazoloquinoline, CGS 9896 (5), a nonsedating anxiolitic devoid of muicle relaxant activity and wi% reduced propensity to potentiate alcohol,l3 which continues to be distinguished from typical BZ anxiolytics in various animal models.14-17 A close analog, CGS 9895 (6) is a potent BZ partial agonist" and a selective antagonist of some anticonvulsants, as is 8-CMC (8).19 Classical BZ

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COOEt

ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21

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Copyright 0 1986 by Academic Press, Inc. All rights of reproduction in any form reserved.

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Hesp, Ed.

structures also remain of interest. SAS 646 (11) and the 'hetrazepine', brotizolam (WE 941, 12) have been introduced a s anxiolytics in Europe. Metaclazepam, (KC-2547, 14) is a putative anxiolytic with less muscle relaxant properties than diazepam or bromazepam.2 o Me

BrO M H ze% Jf

-N

wN2Me -N

R=COOEt A=H

F

v

Loflazepate (CM 6912, 3)is a potent inhibitor of radioligand binding is more to the central BZ receptor, although a metabolite, (CM 7116, effective in potentiating the suppression of guinea pig cerebellar Purkinje cell firing by GABA.21 A series of 1-azacycloalkyl BZs has been reported to have antianxietylantidepressant actions.2 2 The rauwolfia alkaloid, raubasine, can inhibit BZ binding to the receptor competitively and has anticonvulsant activit in v ~ v o . SR ~ ~95195 (17)has been reported to be a BZ antagonist. Pitrazepin a potent competitive GABA-A receptor antagonist, is non-selective and binds to glycine receptors at equivalent concentrations.2 5 The quinoline partial agonist PK 8165, has anxiolytic activity in humans.26 Compound 2 is active in binding assays and animal models . 2 7 "Hetrazepine" 20 has anticonflict and compound 2236 but no anticonvulsant, activity.28 Ro 15-3505 (g)m are BZ antagonists.

E),

Y--

(Is),

- Controversy still surrounds the delineation of BZ receptor subtypes, as assessed by ligand binding studies, and their pharmacological relevance.3 ' 4 The temperature dependence of BZ binding has questioned the physiological relevance of the minutiae generated in bindBZ Receptor Subtypes

Chap. 2

Anxiolytics, Anticonvulsants, etc.

Williams, Yokoyama

13

ing studies,31’32 while the anomalous binding properties of triazolam (2)have been linked to its hypnotic actions.31 New studies have cast doubt on the earlier suggestion that the BZ-1 subset of binding sites constitutes the anxiolytic r e ~ e p t o r . The ~ BZ-1 sites are enriched in the cerebellum, a brain region more involved in motor than in cognitive function. By default, the hippocampal BZ-2 receptor was deemed responsible for the ancillary pharmacology of the BZs. The h notic, zolpidem (SL 80.0750, 24) binds selectively to BZ-1 receptors.33q4 BZ-1 and BZ-2 receptors are each located at pre- and postsynaptic ~ i t e s , ~ The ” ~ ~ chloride channels associated with the central BZ receptor complex appear to exist in multiple forms, their number being eight- and four-fold higher than the respective numbers of BZ and GABA-A receptor^.^' Other studies have shown that the functional state of the chloride channel is markedly dependent on GABA.38-40 Monoclonal antibodies to the bovine central BZ receptor complex interact with four antigenic determinants on the receptor.41 The antibodies cross-reacted with rat and human brain receptor complexes but did not affect BZ binding to these receptors. The molecular weights of the BZ binding site in the central receptor complex, and the picrotoxinin/ barbiturate binding site, are 51K and 138K daltons, respectively, as determined by radiation inactivation studies.42 When isolated by CHAPS solubilization, the BZ receptor from rat brain has a Stokes radius of 7.7 nm and is GABA-sensitive in terms of its binding characteristics; the complex isolated using Triton X-100 has a radius of 6 . 0 nm and is insensitive to GABA.43 The use of protein modifying reagents has further confirmed that the binding site for suriclone on the BZ receptor complex is distinct from that for the BZs ,44 while averruectin interactions with the complex involve a binding site distinct from that for barbiturate^.^^ BZ receptors are present in the pituitary gland.46 M

y

M e o ) e $ -N

.

Me0

CH2CONMe2 CH3

c

24

dNH2 CI

\ I 23

-N

Me0

NN ’,

CICH2CH2CH2COOH

25

OMe

Me0

22

z

Preliminary reports have shown that the BZ receptor can undergo phosphorylation and glycosidases can alter BZ ligand binding to the rece~tor.~’ A comparison of the X-ray structure of the BZ antagonist Ro 15-1788, the pyrazoloquinoline inverse agonist CGS 8216 (1) and members of the p-carboline series has allowed delineation of the receptor site topography for both agonists and antagonists: the model suggested on the basis of this limited SAR has seven conformationally mobile binding points.48 [llC]-Ro 15-1788 has been used to ma BZ receptor sites in human brain using positron emission tomography.49’p0 The GABA effector, valproate has minor tranquilizer activity,51 while GYKI-51 189 (g), a BZ that does not bind to the central BZ receptor, can enhance binding of GABA to a low affinity site.52 This compound is also more active as an anxiolytic/antidepressant than its analog, tofizopam 26. The arylaminopyridazine derivative of GABA, SR 95103 is a potent inhibitor of

(a),

14 -

Section I

- CNS Agents

Hesp, Ed.

GARA-stimulated BZ bindings3 thereby reducing seizure threshold.54 The glucocorticoids, corticosterone and pregnenolone sulfate, enhance binding to the GABA-A receptor.5 5 Other compounds affecting ligand binding to the BZ receptor complex are cannabinoids,56 methylimidazoleacetic acid,57 the antagonist compound 1,58 as wel.1 as several beta-carboline related e n t i t i e ~ . ~ ~ -The ~ l involvement of GABA in the anxiolytic, as opposed to the sedative, actions of BZs has been questioned as has the predictive value of the 'GABA-shift'.62'63 Studies of the effects of GABA on the binding of the "hetrazepines" (vide supra) to central BZ receptors have suggested that facilitation of GABAergic transmission may be related to the hypnotic, rather than the anticonflict or anticonvulsant actions of the B Z S . ~ In ~ this context, binding of compound 12 undergoes a "GABAshift" while the binding of the analo WE 973 ( 1 3 ) T 0 which lacks hynotic activity, is unaffected by GABA.6g' BZ receptor activation has been linked to the modulation of acetylcholine release from rat brain striatal slices.65 Patch-clamping studies in adrenal chromaffin cells have shown that the dose-response curve for GABA-A receptor-activated chloride channels (which are similar to those in the CNS) has a Hill coefficient consistent with a bimolecular interaction: the GABA-induced currents are potentiated by diazepam. 66 Peripheral BZ receptors - Since the discovery of PBZRs in the kidney eight years ago, much effort has been expended in elaborating their physiological significance. This is of relevance in the CNS, since such receptors are present in nervous t i s ~ u e . ~While ~ ' ~ earlier ~ reports classified PBZRs as "acceptor" sites rather than receptors 2-4 studies with the agonist Ro 5 - 4 8 6 4 , and the antagonist PK 1 1 1 9 5 , 1 d y 6 9 ' 7 0 have shown that the receptor may have functional significance. Binding studies have shown PBZRs to be localized in kidney, adrenal cortex, spinal cord, testis, pineal gland and skin. A PBZR can enhance muscimoldependent phospholipase A-2 activation in C6 glioma cells. 7 1 Associations between the PBZR and calcium channels have been reported in cardiac the GH pituitary cell line,72 and glial cell tissue,12'69'70 cultures.73 In guinea pig papillary muscle, the effects of the PBZR antagonist PK 11195, the agonist Ro 5-4864, and the calcium agonist Bay K 8 6 4 4 , have been tentatively linked to a model which relates the PBZR to voltage-sensitive calcium channels (VSCCs) . l 2 However, direct interactions of Ro 5-4864 with VSCCs have also been reported74 and work in leech neurones has indicated a relationship between a micromolar BZ receptor and calcium channels.75 Since clonazepam is effective in this system, the BZ receptor may be of the central type. BZ de ression of calcium conductance in myenteric neurons has been observed.7g PK 11195 may be useful for the treatment of angina and cardiac ischemia.7Q Other effects of BZs in non-neural tissues include the antagonism of the actions of platelet aggregation factorll (an effect that appears to involve the arachidonic acid pathway) ,77 and a chemotactic effect in neutrophils.7 8 BZs also inhibit neurite outgrowth in PC12 cells,79 an action that may be independent of a rece tor-mediated event. Endogenous ligands for the PBZR have been

-

The protein termed DBI (Diazepam Binding Inhibitor) Endogenous ligands has been isolated and shown to consist of 104 amino acid residues.10'82 The peptide, which is located in non-GABAergic neurons in rat cerebral cortex, can elicit proconflict responses when administered to rats. Preliminary studies have shown that two fragments of DBI, an octadecapeptide ( 2 8 ODN) and an octapeptide (ON), have similar activity to that of the parent moeity.82 Monoclonal antibodies to 3-hydroxyclonazepam have

Chap. 2

Anxiolytics, Anticonvulsants, etc.

Williams, Yokoyama

15

been used to identi.fy an endogenous BZ-like factor in mammalian brain.83 Although clonazepam was used to raise the antibodies, they have limited affinity for the parent They bind Ro 5-4864, diazepam, and flunitrazepam but not Ro 15-1788, compound 7 or the beta-carbolines. While reports related to GABA-modulin continue to appear,85 this entity has still to fulfil several of the criteria proposed for endogenous ligands.g6 Gln-Ala-Thr-VaCGly-Asp-VaCAsn-Thr-AspArg-Pro-Gl~Leu-Leu-Asp-Leu-Lys

a

Opiate and thyrotropin releasing hormone (TRH) receptor interactions The antagonistic effects of BZs on the antinociceptive actions of cholecystokinin-8 sulfate have been related to effects on CCK-mediated opioid peptide release-effects that may reflect a non-specific calcium antagonist-like action.g7'88 Naloxone can enhance the de ressant effects of chlordiazepoxide on mouse spontaneous motor activity,8g while hydroxymethylbetacarboline can antagonize the respiratory depressant effects of fentanyl." These findings have led to the suggestion that there may be a "cross reactivity" between BZ and opiate receptors. BZs can interact with central TRH receptor^'^'^^ and chlordiaze oxide is a competitive TRH antagonist in the GH3 pituitary cell line.'3 BZ inhibition of [3H]methyl-TRH binding shows marked regional specificity in brain tissue, with BZs being much less active in amygdala than in ~triatwo.'~ Furthermore, blockade of central TRH receptors was found to have no functional correlation, either biochemical or behavioral, in terms of agonist or antagonist activity.94

*

-

Serotonergic aspects of anxiety Studies on the buspirone analog TVX Q 7821 (2) have shown that this compound is a selective agonist at serotonin 5-HT1A receptors consistent with previous observations that buspirone had serotonin agonist activity." The prototypic 5-HTlA agonist 8-OHDPAT (29)) has also been reported to have anxiolytic a ~ t i v i t y . ~Gepirone ( 3 ) ) ayecond-generation buspirone analog with reduced antidopaminergic activity, is currently undergoing extensive preclinical e~aluation;'~ a related compound (2)) has been reported.8 Binding of 3H-buspirone is high providing in parietal cortex and amygdala (in contrast of that of BZs),' further evidence that buspirone and similar compounds act as "midbrain modulators". Fluprazine (DU 27716, 30) a compound with serotonergic properties has anxiolytic activitygg as does the 5HT2 antagonist,

ritanserin (~),99'100 Compound 32 was reported to be twice as active as chordiazepoxide versus electroshock-induced aggression in mice and was effective clinically.I D 1 Mechanistically, the compound had weak activity at 5-HT2 and D-2 receptors, but like other serotonergics did not (10-'M) affect either BZ or GABA binding to the complex. The clinical attractiveness of the buspirone series of antianxiety agents is clouded by the possibility that their intrinsic antidopaminergic activity may result in extrapyramidal symptomatology.l o * 'l o 3 The reduced incidence of such activity in compounds and 39 may make these second generation analogs of compound 1potentially more attractive clinically.

z7

16 -

Section I

- CNS Agents

Hesp, Ed.

Compound 1 does not induce the serotonin behavioral syndromelo4 and dopaminergic, rather than serotonergic, mechanisms are believed to subserve its activity in a novel acoustic startle model of anxiety.lo5 A selective up-regulation of 5-HT1 receptors in rat frontal cortex has been described with clonazepam, but not with diazepam.lo6 This effect has been related to clonazepam's ability to increase brain serotonin levels. Chronic treatment with compound 2 can reduce cortical 5 - m ~receptors.

-

Behavioral aspects With the shift in focus from BZs to serotonergics and other factors, the classical conflict paradigms are proving to be inadequate as preclinical models of anxiety. As a result, acoustic startle,lo5 distress vocalization,lo7 aggression,lo8 brain stimulation reinforcementlog and defense burying'" paradigms are undergoing evaluation, as are various neophobic models, including arm mazelll and open field behavior. 112 This latter paradigm has shown genetic differences in neophobic behavior. l2 An electrically-induced head turning model in rat has been reported to reflect a functional expression of the BZ receptor complex.113 The evaluation of BZs as antiaggressive agents has been questioned. From behavioral testing of the atypical anxiolytic, compound 30, the term "serenics" has been introduced to describe agents with pronounced antiaggressive, as opposed to anxiolytic , activity. Concurrent biochemical and behavioral studies have led to the identification of an 'anxiolytic locus' in the lateral a m ~ g d a 1 a . l ~The ~ BZ antagonist Ro 15-1788, is undergoing evaluation for the treatment of BZ overdose1" and as a potential analeptic.11' FG-7142, a beta-carboline with anxiogenic activity, can induce 'learned helplessness'.'18

-

Sedative/hypnotics The aminopyridazine SR 41378 (33) has hypnotic activity."' Quazepam has been introduced as a hypnotic. Zopilcone was as effective as temazepam in the treatment of insomnia.lZO The profile of 34 and related analogs is similar t o that of methaqualone.lZ1 3-Hydroxymethylbetacarboline antagonizes the effects of pentobarbital, suggesting a common locus of action at the BZ receptor.122 Reports on the hypnotic activity of SC 33963 (2)continue to appear.123 ZK 93423 (5) is a muscle relaxant.lZ4

Chap. 2

Anxiolytics, Anticonvulsants, etc.

Williams, Yokoyama

a

- Etifoxine

(HOE 36801, 36),125 ZK 91296 and LY reported as antzonvulsants. Chronic treatment with carbamazepine can up-regulate adenosine A-1 receptors.128 Adenosine, which may function as an endogenous anticonvulsant, is released following seizure initiation129'130 and can attenuate, but not prevent postictal spike formation, thereby acting to prevent seizure spread. Prenatal administration of chlordiazepoxide results in a reduced susceptibility to metrazole-induced convulsions in the offspring. This has been correlated with a decrease in the number of BZ receptors in cortex arid cerebellum.131 A deficit in the number of BZ/GABA-A receptor complexes has been reported in substantia nigra and mesencephalic periaqueductal gray matter in the seizure-susceptible gerbil.13* These decreases, which appear to be genetically predetermined, have been suggested to underlie the etilogy of certain types of epileps SKF 89976 (38), a GABA uptake inhibitor, has anticonvulsant activity.yi3 Reports onthe clinical pro- continue to appear.134 file of MK 801 (39) Anticonvulsants

175644

(z)l''have been

-

Novel approaches to anxiety Antagonists of excitatory amino acids can display similiar pharmacology to compounds which facilitate the actions of inhibitory amino acids. In CHZPO3Hz Me Me this context, the N-methyl-DI aspartate antagonist, 2-amino-7( p ) 44p O ~ N ~phosphonoheptanoic ~ ~ O acid (AP7, FHNHZ a , N \ 4 0 ) , has been reported to have COOH Me Me anticonflict activity13= (cf benzodiazepines which facilitate the actions of GABA).136 Mebicar (41) a novel anxiolytic developed in the USSR is a derivative of allantoin, an oxidation product of uric acid.137 References

1. 2. 3. 4. 5. 6.

D.E. W.E. W.J. J.D.

Coodwin. Anxiety, Oxford, New York (1985). Haefley, E . Kyburz, M. Gereke and H . Mohler, Adv. Drug. Res., 14, 165 (1985). S e i g h a r t , Neural T r a n s . , 63, 191 (1985). H i r s c h , K.M. G a r r e t t and B. Beer, Pharmacol. Biochem. .Behav., . ~ . 2 , 681 (1985). J . F . Tallman, and D . W . G a l l a g e r , Ann. Rev. N e u r o s c i . , 8 , 21 (1985). D.P. T a y l o r , M.S. Eison, L.A. R i b l e t and C.P. Vandermaelen, Pharmacol. Biochem. Behav., 23, 687 (1985). 7. T. G l a e s e r and T. T r a b e r , Naunyn-Schmiederg's Arch. Pharmacol., 329, 211 (1985). 8. United S t a t e s P a t e n t 4,507,303 (1985). 9 . A.S. Eison and F.D. Yocca, Eur. J . Pharmacol., 111,389 (1985). 10. E. Costa and A . C u i d o t t i , Biochem., Pharmacol., 34, 3399 (1985). 11. E. Kornecki, Y.H. E h r l i c h and R.H. Lenox, S c i e n c e , 226, 1454 (1984). 12. M . Mestre, T . C a r r i o t , C . B e l i n , A. Uzan, C . R e n a u l t , M.C. Dubroeucq, C . Cureremy, A. Doble and G. Le F u r , L i f e S c i . , 36, 391 (1985). 13. P.S. Bernard, D . A . B e n n e t t , G . P a s t o r , N. Yokoyama and J.M. Liebman, J . Pharmacol. Exp. T h e r . , 235, 98 (1985). 14. D.A. Bennett, L i f e S c i . , 37, 703 (1985). 15. D.J. Sanger, D . J o l y and B . Zivkovic, J . Pharmacol. Exp. T h e r . , 232, 831 (1985).

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- CNS Agents

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2

16. 71. 78.

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83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 91. 98. 99. 100 * 101.

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110. 111.

112. 113. 114. 115. 116.

Johnson, J . K . T . Wang, K . H . Sonnenfeld and S. S p e c t o r , Proc . N a t l . Acad. S c i . U.S.A., 82, 5223 (1985). M. Gavish and F. F a r e s , Eur. 3. Pharmacol., 107,283 (1985). T. Nishikawa, E.H. C ant or and S. S p e c t o r , Fed. P r o c . , 5 , 1830 (1985). H . Alho, E . C ost a, P. F e r r e r o , M. F uj i m oto, D . Cosenza-Murphy and A . G u i d o t t i , S c i e n c e , 2,179 (1985). L . Sangameswaran A . L . De B l a s , P roc. N a t l . Acad. S c i . U.S.A., 82, 5560 (1985). A.L. De B l a s , L. Sangameswaran, S.A. Haney, D. P a r k , C . J . Abraham, J r . and C.A. Rayner, J. Neurochem., 5 , 1748 (1985). F . Va c c a r ino, H . Alho, A . G u i d o t t i and E . Cos ta , SO C. N e uros c i. A b s t r . , lJ, 1122 (1985). M. Williams and S . J . Enna, Ann. Rep. Med. Chem., 5, (1986). K. Kubota, K. Sugaya, I . Matsuda, Y. Matsuoka and Y . Terawaki, Jap: J . Pharmacol. 37, 101 (1985). Kubota, K . Sugaya, N . Sunagane, I . Matsuda and T . Uruno, Eur. J. Pha rma c ol. , 110, 225 (1985). Rodgers, J. R andal l , and B. Kelway, Ne uros c i. L e t t . , 58, 97 (1985). N. Naughton, W.E. Hoffman, P. L arschei d. J.M. Cook, R.F. A l b r e c h t and D. M i l e t i c h , L i f e S c i . , 36, 2239 (1984). N . A . S h a r i f a n d D . R . B u r t , J. Neurochem., 43, 742 (1984). S.M. Simasko and A . H o r i t a , E ur. J. P h a r m a z l . , 98: 419 (1984). A.H. Drummond, Biochem. Biophys. Res. Comm., 127, 6 3 (1985). R.K. R i n e h a r t , B. Barbaz, S . I y e n g a r , F . Ambrose, D . J . S t e e l , R.F. N e a le , B . P e t r a c k , H . B i t t i g e r , P.L. Wood and M . W illia ms , J. Pharmacol. Exp. T h e r . , i n p r e s s (1986). S . H j o r t h and A. C a r l s s o n , Eur. J. Pharmacol., 83, 299 (1985). J . A . E n g e l, S . H j o r t h , K . Svensson, A. C a r l s s o n and S . L i t j e q u i s t , Eur. J . Pha rma c o l ., 105,365 ( 1 9 8 5 ) . M.S. E i s o n , D.P. T ayl or and L . A . R i b l e t , i n "Drug Discovery and Development" M . Williams and J . B . Malick, E d s . , Humana P r e s s , C l i f t o n , N J , 1986 i n p r e s s . B. O l i v i e r and L.D. B radford, AggreS. Behav., lo, 165 (1985). F.C. C o l p a e r t , T.F. Meert, C . J . E . Niemegeers and P.A.J. J a n s s e n , Psychopharmacol., 86, 45 (1985). E L . Ceulemans, M.L. Hoppenbrouwers, Y . G . G e lde rs and A . J . Reynt l e n s , Pharmacop s y c h i a t r . , E , 303 (1985). K.G. Lloyd, H. Depoort ere, B. S c a t t o n , H. Schoemaker, B. Zivkovic , Ph. Manoury, S.Z. Langer, P.L. M o r s e l l i and G . B a r t h o l i n i , Pharmacol. Biochem. Behav., 2 , 645 (1985). D . A . Downs, S . E . Harri gan and T.G. H e f f n e r , SO C. N e uros c i. A b s t r . , lJ. 426 (1985). H.L. Goldberg, Pharmacotherapy, 4, 315 (1984). P. S k o ln i c k, B.A. Weismann and-M.B.H. Youdim, B r . J. Pharmacol., 86, 637 (1985). M . D a v i s, J . H . Kehne and J . V . C a s s e l l a , SOC. N e uros c i. A b s t r . , l J , 426 (1985). H . R . Wagner, A . Reches and S . Fahn, Neuropharmacol., 2, 953 (1985). C . J . Gardner, Pharm. Meth., 14, 181 (1985). B. O l i v i e r , R . V a n o o r s c h o t a n d L.D. Bra dford, Aggress. Behav., 11, 169 (1985). J . M . Liebman, Neurosci . Biobehav. Rev., 9 , 75 (1985). D . T r i e t , N eurosci . Biobehav. R ev., 11, 203 (1985). S . Pellow and S.E. F i l e , SOC. Neurosci . A b s t r . , 11,273 (1985). A. D e l i n i - S t u l a and C . Hunn, Behav. Neural B i o l . , 206 (1985). J . M . G o l d s t e i n , E.B. S u t t o n and J . B . Malick, L i f e S c i . , 38. 459 (1986). R . J . Rodgers and A . J . Waters, Neurosci . Biobehav. Re v. , 2 1 (1985). S.R. Thomas, M.E. L e w i s and S.D. I v e r s e n , Bra in Res., 342, 85 (1985). P. Hofer and G . S c o l l - L a v i z z a r i , Arch. I n t . Med., 145, 663 (1985).

m.

5,

5

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117. P.M. Lauven, H . Schwilden, H . S t o e c k e l and D.J. G r e e n b l a t t , A n e s t h e s i o l . , 8 , 61 (1985). 118. R . C . Drugan, S.F. Maier, P. S k o l n i c k , S.M. Paul and J . N . Crawley, Eur. J. Pharmacol., 113,453 (1985). 119. V. S a n t u c c i , M. F o u r n i e r , J . P . Chambon and K . B i z i e r e , SOC. Neurosci. A b s t r . , 11, 424 (1985). 120. D. Wheatley, Br. J. P s y c h i a t r . , 146, 312 (1985). 121. W . J . Houlihan, J . H . Gogerty, E.A. Ryan and G. S c b m i t t , J. Med. Chem., 28, 28 (1985). 122. R.F. A l b r e c h t , J . Cook, W.E. Hoffman, P. L a r s c h e i d , D . J . M i l e t i c h and N. Naughton, Neuropharmacol., 24, 957 (1985). 123. Clin. Pharmacol. Ther., 38, 602 (1985). 124. T. Klockgether, I. Pardowitz, M . Schwarz, K-H. Sontag and L. T u r s k i , B r . J. Pharm., 86, 357 (1985). 125. KJ.Kruse and H. Kuch, Arm. F o r s c h . , 35, 133 (1985). 126. T. Klockgether, M. Schwarz, L . T u r s k i , S . Wolfarth and K-H. Sontag, Eur. J. Pharmacol., 110, 309 (1985). 127. D.W. Robertson, J . H . K r u s h i n s k i , E . E . Beedle and R . C . Rathbun, A b s t r . 189th Am. Chem. SOC. Meeting, Miami Beach, A p r i l , 1985, MEDI 32 (1985). 128. P . J . Marangos, S.R.B. Weiss, P. Montgomery, J . P a t e l , P.K. Narang, A.M. Cappabianca and R.M. P o s t , E p i l e p s i a , 26, 493 (1985). 129. M. Dragunow, G.V. Goddard and R . L a v e r t y , E p i l e p s i a , 3, 480 (1985). 130. T.F. Murray, D. S y l v e s t e r , C.S. Schutz and P. S z o t , Neurophannacol., 2,761 (1985). 131. M. Gavish, N . Avnimelech-Gigus, J . Feldon and M. Myslobodsky, L i f e S c i . , 36, 1693 (1985). 132. R.W. Olsen, J . K . Walmsley, R . T . McCabe, R . J . Lee and P . Lomax, Proc. N a t l . Acad. S c i . U.S.A., 82, 6701 (1985). 133. F.E. A l i , W.E. B o n d i n e l l , P.A. Dandridge, T.S. F r a z e e , F. Garvey, G.R. G i r a r d , C. K a i s e r , T.W. Ku, T.T. L a f f e r t y , G . I . Moonsammy, H - J . Oh, J.A. Rush, P.E. S e r l e r , O . D . S t r i n g e r , J.W. Venslavsky, B.W. Volpe, L.M. Yunger and C . L . Z i r k l e , J . Med. Chem., 28, 653 (1985). 134. H.B. Hucker, B.M. Sweeney, S.A. R e i n e s , S.C. Wheeler and R.K. Ferguson, Fed. P r o c . , 44, 1821 (1985). 135. E A . Bennett, C.L. C o r r a d i and J . Lehmann, SOC. Neurosci. A b s t . , 11, 106 (1985). 136. S. McPherson, P.L. Wood and J. Lehmann, SOC. Neurosci. A b s t r . , 824 (1985). 137. Drugs F u t u r e , lo, 464 (1985).

11,

Chapter 3. Analgesics, Opioids and Opioid Receptors Roger James ICI Pharmaceuticals Division, Macclesfield, Cheshire, England

-

Introduction Opioid research continues to dominate the search for new analgesic drugs and to provide further insight into the nature and function of endogenous opioid systems. The proceedings of the 1985 International Narcotics Research Conference have been published1 together with those of a symposium on multiple opioid receptors2. The history of opioid research, as reflected in the discovery of buprenorphine, has been a s ~ e s s e d .Methods ~ available for evaluating opioid analgesics and antagonists have been reviewed4 and a collection of articles on agonistantagonist analgesics has been made available.5 Reviews have been provided on the mechanisms of pain and opioid induced analgesia,6 particularly at the spinal level 7p8 the role of opioid receptor sub-types in relation to antinociception,4 the significance of o ioid-neurotransmitter interactions in analgesia, tolerance and dependencero and the role of opioid pe tides and antagonists in circulatory shock11 and in respiratory function.lg The implications of the pharmacology of quaternary antagonists for their use in future experiments have been discussedl3 and the evidence for stereospecific opioid receptors on excitable cell membranes has been assessed. 14 CLINICAL HIGHLIGHTS Non-opioid analgesics - Reviews have appeared on the harmacology and efficacy of the NSAIDs, tiaprofenic acid15 and suprofenf6 , and on the animal pharmacology of ketorolac tromethamine(l)l7 which has been shown to be as effective (10mg and 3Omg, im) as morphine (12mg, im) in the first 6 hours following surgery in man.18 In patients with cancer pain, diclofenac (75mg, im) was claimed to be significantly better than pentazocine (30mg, im) with fewer side effectslg and ibuprofen has been used to improve the efficacy of oral narcotics without increasing side effects.20 Indoprofen (200mg, PO) was found to be superior to aspirin (600mg, PO) in the relief of dental pain21 and as effective in post-partum episiotomy pain.22 Lysine acetylsalicylate has been reported to be an effective analgesic when given by iv infusion for the treatment of post-operative pain.23924 A brief review has been provided for emorfazone (21, an antiinflammatory analgesic which increases vascular permeability and inhibits bradykinin release without affecting prostaglandin biosynthesis.25

-1

-2

A pilot study has shown that epidural somatostatin afforded complete analgesia without serious side effects after abdominal surgery in man.26 Ceruletide has been recommended as a first choice analgesic agent in the treatment of biliary colic pain,27 whilst infusion of salmon calcitonin (iv) has been shown to be effective in the relief of bone pain in patients ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21

Copyright 0 1986 by Academic Press, Inc. AU rights of reproduction in any form reserved.

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with osteolytic metastases.28 The methods available for the assessment of pain in healthy volunteers have been reviewed with the emphasis on E . E . G . analysis as a powerful tool for identifying weak analgesic effects29 and a critical review of pain perception and analgesia as functions of circadian rhythm has been provided .30 Opioid analgesics - Newer methods of opioid delivery, including controlled release formulation, sublingual dosing, intravenous infusion and spinal administration, have been revie~ed.~l The strategy of patient-controlled analgesia has been discussed32 and its application illustrated by morphine infusion (iv) in post-operative pain relief .33 Epidural injections of morphine administered "on demand", either alone or as a supplement to an epidural infusion, gave good post-operative analgesia with a low incidence of respiratory depression after a variety of surgical procedures.34,35 Significantly less nicomorphine was needed for adequate ost-operative analgesia when given by epidural, rather than im, injection.56 Preliminary studies showed that dynorphin A (Dyn A ) and human B-endorphin (BH-EP) reduced intractable pain without side effects, when administered intrat h e ~ a l l y . ~ ~In double-blind studies, ciramadol (6Omg, im) compared favorably with morphine (lOmg, im) as a post-operative analgesic,38 while dezocine appeared slightly more potent than morphine on a mg basis and gave a more rapid onset of analgesia.39 The pain relief provided by viminol (Smg, iv) was not significantly different from that obtained with pentazocine (3Omg, iv) post-operatively, though the incidence and severity of side effects was less.40 Buprenorphine has been shown to be satisfactory for major surgery as part of a balanced anaesthetic te~hnique.4~ It has been suggested that the differences in analgesic profiles of buprenorphine and fentanyl in man can be explained in terms of their pharmacodynamic properties as observed in in vitro receptor binding assays.42 Reviews have afjeared on the animal pharmacolo y and clinical evaluation of sufentanil, naltrexone44 and meptazinol.48 In recent studies meptazinol (175rng, im) was equivalent to morphine (IOmg, im) in the relief of severe post-operative pain46 while lOOmg (im) was equivalent to, or better than, morphine (15mg, im> in the treatment of pain due to traumatic injury.47 The cholinergic component of meptazinol has been ascribed to its inhibitory effect on cholinesterases.48 OPIOID RECEPTOR STUDIES Receptor isolation - Progress has been reported towards the purification of sufficient binding-site material for sequencing, using techniques involving detergent solubilization, affinity chromato raphy and gel electrophoresis of rat brain membranes. When [D-Ale2-Leu Ienkephalin (DALE) was used as the affinity ligand,49 a 450-fold purification of binding sites with molecular weight 62,000 was a~hieved.5~ Studies with hybromet (31, an opioid claimed to have high af€inity €or ~-receptors,5~afforded a 500fold enrichment of a single class of high affinity sites comprising three sub-units of molecular weights 94,000, 44,000 and 35,000, respectively.52 A 3,200-fold purification of an opioid binding fraction was obtained with 6-succinylmorphine as the ligand and conditions which a1 lowed co-elution of acidic lipids. The purified material exhibited high affinity, stereospecific, Na+-dependent binding of a variety of opioids, with the same rank order of potency observed for membrane bound 0-receptors .53 The potent &selective acylating agent 4 has been used to purify an opioid receptor sub-unit from NC108-15 neuroblastoma-glioma hybrid cells by 30,000-fold, affording a homogeneous protein with molecular weight 58,000, which showed a strong tendency to dimerise.54 In another study, irreversible cross-linking with [1271]-B" EP, followed by gel electrophoresis,

B

Chap. 3

Analgesics, Opioids and Opioid Receptor8

James

23

revealed major bands with molecular weight 65,000 from rat thalamus and 53,000 from NG108-15 cell membranes, considered to be p- and 6-sites, respectively.55 B-Naltrexyl-6-ethylenediamine was used as the affinity ligand for the isolation of p-sites from bovine striatum, affording 60-75,000 fold purification of a protein with molecular weight 65,000.56

un

-

WCH *CIH

C H ~ C ,CH H

OCHx \CH,HgBr

M

C H :

Receptor classification and pharmacology - The use of ligands with limited selectivity (has been reported.136

(a>,

-5

-6 -,

R=CH,

,

I)

R

-s

R = C H I , X=SCOC,Hs

lo

R =CHI, X=oH

R'=H

R =CHzd

,R'=H

R = C H ? ~ , R'=COCH~

-

= (CH&F, X=OH

11

The synthesis and evaluation of tritiated opioids which are selective for 8- and k-receptors has been reported. Studies with [3H]-[D-Pen2,5]enkephalin ([3H]-DPDPE) in NG108-15 cells have confirmed that it is a potent and selective 6-ligand.l37 It has been suggested that [3H]-DPDPE can be used to examine &receptors in regions containing a high proportion of v-sitesl38 and it has been utilised to demonstrate a unique distribution of &sites in rat brain.139 [3H]-[D-Thr2,Leu5]enkephalyl-Thr6 has been proposed as an alternative ligand by other workers who have claimed that [3H]-DPDPE exhibits low 6-affinity in NG108-15 cells, thereby inducing high experimental errors and cancelling the benefits of its &selectivity.140 [3H]-Tifluadorn was shown to be more specific for the k-receptor than [3H]-bremazocine or [3H]-EKC141 but none of these ligands was said to be selective enough for meaningful studies.l42 An analogue of U50488H, [3H]-U69593 (111, has recently been shown to bind with high affinity to guinea-pig, mouse and rat brain membranes, with a high preference for k- over ~ - s i t e s . l ~ ~ Novel compounds - The (+)-9-amino analogue 11 was the most potent of a series of 1,5-methano-l,4-benzodiazocines tested in a mouse writhing assay.l44 8-Benzoyl thio-2,6-methanobenzazocine (9) was half as active as metazocine (lo) and less toxic in the mouse. 145 The (-1-acetylmorphinan derivative 12 was orally active and comparable in potency to morphine in analgesic

42SN -

12

4 2 q 5%

tests naloxone binding, yet with dependent little or no de and endence liability in morphine rats.p46

\4

NHZ

CHf $ $N

COWS OH

r3

li

'

OH

is

Analgesic activity equivalent to morphine has been reported for the racemic 9a-hydroxyphenylmorphinan If! whereas the corresponding gp-isomer

Chap. 3

James 2 J

Analgesics, O p i o i d s and Opioid Receptors

was virtually inactive.147 The (R)-Diels-Alder adduct 15, derived from 6-deoxythebaineY was a potent analgesic in a rat tail-flick model (2200 x morphine, sc). 148 Selective k-antagonist activity has been claimed for TENA (161, a dimeric B-naltrexamine analogue which is 27-fold more effective vezus U50488 than morphine in vitro.149 Electron acceptor properties of the aromatic ring and amine functions, and conformational energy constraints, appear to play a significant role in determining p-binding affinity in a series of trans-N-[2-(methylamino)cyclohexyl]benzamides (17).l50

--

[

&

N

cH'cHac]

g

'

OH

2

11

le

The rigid 131nembered ring compound, H-Tyr-D-Orm-Phe-Adp-NH2, has been claimed to be one of the most selective p-ligands known, while the more flexible peptide H-Tyr-D-tys-Phe-dlu-NH2 (15-membered ring) showed no preference for M- over 6 - receptors in binding studies.151 In addition, efficient binding and p - s e l e c t i v i t y h a s b e e n d e m o n s t r a t e d for the somatostatin analogue, H-D-Phe-C's-Tyr-D-Trp-Lys-Thr-Peh-ThrNH2 (CTP) which contains a 20-membered ring.rS2 Studies with modified analogues of dermorphin have shown that the guanidine 19 is more potent than the parent peptide in producing both analgesia and akinesia in ~ a t s , l 5while ~ the partially retro-inverso tetrapeptide 20 is equivalent to dermorphin in the mouse tail-flick test (icv) and five times more potent in vitro.l54 The pentapeptide dimer 2 was half as potent as DALE-amide in a rat analgesic assay (icv) ,155 whereas the tripeptide dimer 22 approached morphiceptin in terms of potency and u-selectivity in rat brain and NG108-15 cell binding assays. 156 (TYP D- AI~-GIY-X

X-Tyr - D-Ala-Phe-Y

18

-

X = H I Y=Gly -Tyr -Pro -Ser -NH,

1 2

X=HzN> ,Y=Gly-Tyr-Pro-Sir-NH, HN X= H I Y=NHCH,NHCO

2_0

-CH, f

2_!

X= Phe-Leu-NH

L 2

X= NH

-8

References

1 . Symposium Report in Alcohol Drug Res., 6 , 63-252 (1985/86). 2. Symposium Report in Fed. Proc., 44, 2851-2862 (1985). 3. J.C. Lewis in "Medicinal Chemistry: The Role of Organic Chemistry in Drug Research", S.M. Roberts and B.J. Price, Eds., Academic Press, London and Orlando, 1985, p119. 4. E.F. Hahn, Methods Find. Exp. Clin. Pharmacol., 7 , 373 (1985). 5. Conference Articles in Drug Alcohol Depend., g,-221-431 (1965). 6. T.W. Smith, Mol. Aspects Med., l , 509 (1984). 7 . T.L. Yaksh and R. Noueihed, Annu. Rev. Pharmacol. Toxicol., 25, 433 (1985). 8. R . Quirion, Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 8 , 5 7 1 (1984). 9. H.W. Kosterlitz and S.J. Paterson, Philos. Trans. R. SOC. Lzndon, Ser. B, 308. 291 (1985). 10. K.H. Jhamandas, Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 5, 565 ( 1 9 8 4 ) . 11. C.J. Hinds, Br. J . Hosp. Med., ", 233 (1965). 12. D.S. Malcolm and J.W. Holaday, Sernin. Respir. Ned., 7 . 8 1 ( 1 9 8 5 ) . 13. D.R. Brown and L.I. Goldberg, Neuropharmacology, 24,-181 (1985). 14. G.B. Frank, Can. J . Physiol. Pharmacol., 63, 102371985). 15. E.M. Sorkin and R.N. Brogden, Drugs, 29, 3 8 (1985). (1985). 16. P.A. Todd and R.C. Heel, Drugs, 30,

5n

28

Section I

- CNS Agents

Hesp, Ed.

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x,

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Analgesics, Opioids and Opioid Receptors

70. 71. 72. 73.

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3

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117. L.R. Watkins, I.B. Kinscheck, G. Rosenquist, J. Miller, S . Wimberg, H. Frenk, E. Kaufman, R. Coghill, S.N. Suberg and D.J. Mayer, Ann. N.Y. Acad. Sci., 448, 676 (1985). 118. D.D. Price, A. von der Gruen, J. Miller, A. Rafii and C. Price, Anesth. Analg., 64, 801 (1985). 119. J.-C. Schwartz, J. Costentin and J.-M. Lecomte, Trends Pharmacol. Sci., 5, 472 (1985). 120. D.A. Evans, D.J. Mathre and W.L. Scott, J. Org. Chem., 1830 (1985). 121. L.G. Mendelsohn, B.G. Johnson, W.L. Scott and R.C.A. Frederickson, J. Pharmacol. Exp. Ther., 234, 386 (1985). 122. W.L. Scott, L.G. Mendelsohn, M . L . Cohen, D.A. Evans and R.C.A. Frederickson, Life Sci., 2 , 1307 (1985). 123. M.-C. Fournie-Zaluski, A. Coulaud, R. Bouboutou, P. Chaillet, J. Devin, G. Wakaman, J. Costentin and B.P. Roques, J. Med. Chem., 28, 1158 (1985). 124. K.-S. Hui, T. Gioannini, M. Hui, E.J. Simon and A. Lajtha, Neurochem. Res., lJ, 1047 (1985). 125. A. Goldstein, R.W. Barrett, I.F. James, L.I. Lowney, C.J. Weitz, L.L. Knipmeyer and H. Rapoport, Proc. Natl. Acad. Sci. USA, 82, 5203 (1985). 126. K. Oka, J.D. Kantrowitt and S . Spector, Proc. Natl. Acad. Sci. USA, 82, 1852 (1985). 127. H.W. Kosterlitz, Nature, 317, 671 (1985). 128. A.E. Takemori and P.S. Portoghese, Annu. Rev. Pharmacol. Toxicol., 25, 193 (1985). 129. D.E. Gmerek and J.H. Woods, J. Pharmacol. Exp. Ther., 235, 296 ( 1 9 8 n . 130. A. Dray, L. Nunan and W. Wire, Life Sci., 36, 1353 ( 1 9 m . 131. R.F. Dannals, H.T. Ravert, J.J. Frost, A.A. Wilson, H.D. Burns and H.N. Wagner, Int. J. Appl. Radiat. Isot., 36, 303 (1985). 132. S . K . Luthra, V.W. Pike and F. Brady, J. Chem. SOC., Chem. Commun., 1423 (1985). 133. H.D. Burns, J.R. Lever, R.F. Dannals, J.J. Frost, A.A. Wilson, H.T. Ravert, 8. Subramanian, S.E. Zemyan, B. Langstrom, and H.N. Wagner, J. Labelled Compd. Radiopharm., 21, 1167 (1984). 99 (1985). 134. T.R. Burke, KX. Rice and C.B. Pert, Heterocycles, 135. A.L. Feliu, M . J . Holland, K.D. Carr, J.S. Fowler and E.J. Simon, Res. Commun. Chem. Pathol. Pharmacol., 2, 323 (1985). 136. M.A. Channing, W.C. Eckelman, J.M. Bennett, T.R. Burke and K.C. Rice, Int. J. Appl. Radiat. Isot., 2, 429 (1985). 137. K. Akiyama, K.W. Gee, H.I. Mosberg, V.J. Hruby and H.I. Yamamura, Proc. Natl. Acad. Sci. USA, 82, 2543 (1985). 138. R. Cotton,x.W. Kosterlitz, S . J . Paterson, M . J . Rance and J.R. Traynor, Br. J . Pharmacol., g ,927 (1985). 139. K. Gulya, D.R. Gehlert, J.K. Wamsley, H . I . Mosberg, V.J. Hruby, S.P. Duckles and H.I. Yamamura, Eur. J . Pharmacol., 111,285 (1985). 140. P. Delay-Goyet, J.4.Zaiac, P. Rigaudy, B. Foucaud and B.P. Roques, FEBS Lett., 183, 439 (1985). 141. W.P. Burkard, P.M. Huller and N. Fluck, J. Recept. Res., 4, 165 (1984). 142. S . J . Paterson, A.D. Corbett, M.G.C. Gillan, H.W. Kosterlitz, A.T. McKnight and L.E. Robson. J. Recept. Res., 5, 143 (1984). 143. R.A. Lahti, M.M. Mickelaon, J.M. McCall and P.F. von Voigtlander, Eur. J . Pharmacol., 109, 281 (1985). 144. Gubitz, J. Med. Chem., 28, 728 (1985). 145. M. Hori, M. Ban, E. Imai, N.Twata, Y. Suzuki, Y. Baba, T. Morita, H. Fujimura, M. Nozaki and M. Niwa, J. Med. Chem., 28, 1656 (1985). 146. E. Mohacsi, J. O'Brien, J. Blount and J. Sepinwall, J. Med. Chem., 28, 1177 (1985). 147. H. Awaya, E.L. May, A.E. Jacobson and M.D. Aceto, J . Pharm. Sci., 1867 (1984). 148. L.L. Knipmeyer and H. Rapoport, J. Med. Chem., 28, 461 (1985). 149. P.S. Portoghese and A.E. Takemori, Life Sci., L q 801 (1985). 150. B.V. Cheney, J. Szmuszkovicz, R.A. Lahti and D.A. Zichi, J. Med. Chem., 28, 1853 (1985). 151. P.W. Schiller, T.M.-D. Nguyen, C. Lemieux and L.A. Maziak, J . Med. Chem., 28, 1766 (1985). 152. J.T. Pelton, K. Gulya, V . J . Hruby, S.P. Duckles and H.I. Yamamura, Proc. Natl. Acad. Sci. USA, 82, 236 (1985). 153. M.A. Cervini, A.C. Rossi, G. Perseo and R. de Castiglione, Peptides (Fayetteville, N.Y.), 6 . 433 (1985). 154. S . Salvzdori, M. Marastoni, G. Balboni, G.P. Sarto and R. Tomatis, J'. Med. Chem., 28, 769 (1985). 155. Costa, M. Wuster, A. Herz, Y. Shimohigashi, H.-C. Chen and D. Rodbard, Biochem. Pharmacol., 2, 25 (1985). 156. R.A. Lutz. R.A. Cruciani, Y. Shimohigashi, T. Costa, S . Kassis, P . J . Munson and D. Rodbard, Eur. J. Pharmacol., 111, 257 (1985).

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Chapter 4. Cognitive Disorders Fred M. Eershenson, John G. Marriott, and Walter H. Moos Warner-Lambert/Parke-Davis, Ann Arbor, MI 48105 Introduction - Memory dysfunctions have been reviewed from preclinical and clinical perspe~tives.l-~ No effective therapy exists for primary degenerative dementia (PDD, Alzheimer's disease), mild (or minimal) memory impairment (benign senescent forgetfulness), or for multi-infarct dementia (MID). However, a better understanding of these disorders and their prevalence, of the biological changes accompanying cognitive impairment and decline, and the development of animal models based on increasing knowledge of affected brain systems, gives hope that new treatments based upon rational approaches will soon be available.

PDD remains the focus of most clinical research on cognitive disorders, but the pseudo-dementias, Korsakoff's syndrome, geriatric depression, and attentional deficit disorder are beginning to receive appropriate attention. Development of effective therapy for PDD is hindered by unknown (perhaps multiple) etiologies, the absence of efficacious agents to validate preclinical models, and the lack of early, reliable diagnostic methods. Possible causes of PDD include genetic predisposition, altered proteins (e.g. amyloid), infectious agents, toxins, blood-flow disorders, neurotransmitter abnormalities, and multiple f a ~ t o r s . ~ , ~ Cholinergic system - The cholinergic hypothesis7 remains a viable explanation for memory deficits in PDD, but it is unlikely to account for the entire range of biochemical, pathological, anatomical, and pharmacological deficits in dementia.8-11 Clinical studies in PDD with muscarinic a onists (e.2. RS-86, 1 and intracranially-infused bethanecol, 2 ) ,I f , chol i ne s t e ra se inhibitors (e.g. physostigmine, 3),14,15 and cholinergic releasing agents (e.g. 4-aminopyridine)16 s h o w e d significant , albeit weak activity. Cholinergic precursors such as choline (Ch) were inactive.I f Minaprine (i),which facilitates serotonergic and dopaminergic neurotransmission, and also has "procholinergic" activity, may be more effective in MID than in PDD.18*19

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32

Section I

- CNS Agents

Hesp, Ed.

Scopolamine challenges represent a potential diagnostic tool for P D D patients may be supersensitive to muscarinic antagonists because of their underlying cholinergic def In vivo imaging of muscarinic receptors in a PDD patient, using single photon emission computed tomography showed impaired binding of 1231-labeled quinuclidinyl benzilatef21 PDD.

Animal models for cognitive disorders remain an area of intense research, but an appropriate model for P D D does not exist. Physostigmine and cholinergic ventral forebrain grafts into the neocortex alleviate memory deficits caused by ibotenic acid lesions of the nucleus basalis of Meynert in rats as measured by passive a ~ o i d a n c e . ~Ibotenic ~ , ~ ~ acid lesions of the basal forebrain impair serial reversal learnin in marmosets with low doses of scopolamine that do not affect controlsj4 Ibotenic acid lesions of the nucleus basalis disru t and physostigmine enhances, performance on delayed matching in rats.f5:26 In the rat, functional and neurochemical cortical cholinergic impairment results from lesioning the nucleus basalis magnocellularis with kainic or quinolinic acid.27 Cholinergic neurons of the basal nucleus degenerate following kainic or N-methyl-D-aspartic acid application to rat cerebral cortex.28 Aziridinium analogues of choline (AF64A, 2)29and oxotremorine (BM130A, 5)30may be useful in developing animal models of cholinergic hypofunction. AF64A causes long-lasting, marked reductions in acetylcholine (AcCh) levels and release, in high affinity Ch uptake, and in Ch acetyltransferase (ChAcT) activity, with no effect on muscarinic receptor binding. Use of the choline false precursor, N-aminodeanol ( I ) ,was proposed for development of animal models of cholinergic h y p o f ~ n c t i o n . ~Inbred ~ strains of rodents may ultimately be useful in establishing new models of cognition sensitive to cholinergic agents.32

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Muscarinic receptors were r e ~ i e w e d .Several ~ ~ ~ ~ studies ~ reported functional and biochemical bases for multiple muscarinic r e c e p t o r ~ , ~ 5 , ~ ~ but classification problems remain.37 3 3 8 Reductions in M2 receptor number and in ChAcT activity are observed in cortical samples from PDD patients and from rats cholinergically denervated with ibotenic acid. M1 receptors are unchanged. M2 receptors may regulate AcCh release with M1 receptors facilitating postsynaptic cellular e x ~ i t a t i o n . ~ ~ Theoretical methods were used to describe cholinergic neurotransmitter receptor interactions.40,41 Analogues of arecoline (5) were evaluated in smooth muscle and cardiac tissue preparations: examples included the dihydro derivative, esters of arecaidine and isoarecaidine 11 and 3, the thiane 5, and the rigid analogue 16.42 The deconjugated and 5-substituted derivatives 15, 9, and 10 were studied as y-aminobutyric acid uptake inhibitors, but cholinergic activity was not in~estigated.~~ Combinations of agonists (e.g. arecoline plus oxotremorine) display supra-additive enhancement of memory in a mouse T-maze active avoidance paradigm.44

Chap.

4

Cognitive Disorders

Hershenson, Marriott, Moos

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Most research on cognition and the cholinergic system has focused on muscarinic receptors. However, nicotinic receptors are increasingly of interest as evidence accumulates for changes in both muscarinic and Nicotine affects attention, memory, and nicotinic receptors in PDD.51 rapid information processing in human^,^^^^^ and learning and memory in mice as measured by passive avoidance.54 It also stimulates AcCh r e l e a ~ e , ~ 5and, in humans, counteracts depressed performance caused by scopolamine.56 The cholinergic system interacts with several other neurochemical s y ~ t e m s . ~Examples ~ , ~ ~ include serotonin,59 amino acids,60 adenosine,61 adenylate cyclase, and phosphodiesterase (PDE).62 The potential exists, therefore, for many classes of agents to alleviate the cholinergic deficit in PDD. Nerve growth factor (NGF) may be involved in the normal functioning of forebrain cholinergic neurons as w e l l a s in neurodegenerative disorders. The biochemical and neurochemical effects of NGF on ChAcT a ~ t i v i t y and ~ ~ ,in~ adult ~ rats with fimbria lesions reported to be a were described.65 Bifemelane (MCI-2016,

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Section

I

- CNS Agents

Hesp, Ed.

“cholinergic potentiator,” ameliorates age-related decreases in AcCh release and exerts a protective effect on cerebral ischemia in gerbils.66 Chronic administration of the thiamine derivative salbutiamine (25) improves long-term memory in mice, possibly by a cholinergic mechanism.67 0

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Biogenic amines - Clonidine (26) ameliorates cognitive deficits in aged monkeys on a delayed response task. The site of action may be the prefrontal cortex where catecholaminergic neurites are found in senile plaque^.^^,^^ However, clonidine impaired paired-associate learning but had no effect on short or long-term memory in normal humans.70

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a specific inhibitor of neuronal serotonin (5HT) Alaproclate reuptake, may have a positive effect on emotional functions in PDD;71 others report little effect in MID and PDD,72 Zimeldine ( g ) ,another 5HT reuptake blocker, has no effect on memory or reaction time in PDD.73 , selectively The hallucinogenic amphetamine derivative MDA ( g )which destroys serotonergic nerve terminals, may aid i n developing animal models of serotonergic defi~it.7~

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28 -

29 -

Neuropeptides - Somatostatin-like immunoreactivity (SLI) is reduced in parietal but not frontal cortex, and in the hippocampus and putamen in PDD.75,76 Decreases in somatostatin receptor number correlate with SLI decline, suggesting either degeneration of postsynaptic neurons, or increased somatostatin release leading to posts naptic d o w n r e g ~ l a t i o n . ~SLI ~ is present in neuritic and a subclass of somatostatin-containing neurons selectively affected in PDD contains neuronal tangles.80 Low cerebrospinal fluid (CSF) levels of somatostatin were found in PDD patients.81 The somatostatin analogue L-363,586 (30) did not improve memory impairment in PDD patients, but the absence of side effects suggests that higher doses should be tried.82 Evaluation of linear and cyclic forms of somatostatin, as well as certain fragments (somatostatin 3-6, 7-10), indicates that the entire peptide sequence is required for prevention of electroconvulsive shock (ECS) induced retrograde amnesia in rats.83

plaque^,^^.^^

730

(NMe)Ala-Tyr-D-Trp-Lys-Val-Phe

Chap. 4

Cognitive Disorders

Hershenson, Marriott, Moos

35

Vasopressin (VP) enhances memory though probably not by central mechanisms. Its behavioral effects may involve peripheral reinforcement and central modulation of arousal.84 The VP analogue DDAVP (31) facilitated memory in males,85 but not in females.86 DDAVP did not improve the memory impairment of chronic schizophrenic^,^^ nor was it effective in reversing ethanol-induced deficits in memory or cognitive was not function in normal subjects.88 Another VP analogue, DGAVP effective in PDD or Korsakoff's DiseasenBgIn a separate study, DGAVP produced slight improvement in list learning of low imagery words.90

(s),

I

I

S-(CH2)2C(=O)-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-GlyNH2

I

I

HCys-Tyr-Phe-Gln-Asn-Cys-Pro-ArgOH

32

2

HMet(S=O)-Gln-His-Phe-Lys-Phe

2

(x),

ORG 2766 a synthetic analogue of ACTH 4 - 9 , was well tolerated but failed to produce significant effects on cognitive function in PDD.91 ORG 2766 was not beneficial on impaired performance related to working overnight or disturbed sleep.92 It did not reduce severity of depression o r anxiety,93 or improve learning, consolidation, or retrieval of memorized material in the elderly, although a higher degree of sustained attention was noticed during drug treatment.94 CSF levels of ACTH are low in PDD.95 %-Endorphin produces a retrograde amnesia in animals which is blocked by opiate antagonists (e.g. naloxone) and by cholinergic agents (e.g. oxotremorine, p h y s o ~ t i g m i n e ) . ~ Dynorphin ~,~~ 1-13 does not cause retrograde amnesia in rats.98 CSF levels of B -endorphin are low in PDD and MID, but levels of 8-lipotro in are unchanged.99 Naloxone did not improve impaired cognition in or in depressed patients after ECS therapy.lol The therapeutic potential of thyrotropin releasing hormone (TRH) and its analo ues in treating PDD and amyotrophic lateral sclerosis was reviewed. l o g T w o stable TRH analogues w e r e evaluated against experimentally-induced spinal trauma in cats: CG-3509 (34)improved neurologic recovery but MK-771 (35)did

CCK-8 (cholecystokinin-8; sulfated and nonsulfated) was marginally active in preventing ECS-induced amnesia in rats (i.c.v.), and may indirectly influence memory.lo4 CSF levels o f vasoactive intestinal polypeptide are unchanged in PDD, but reduced in MID.105 Neuropeptide Y (NPY) may inhibit memory retention in PDD.lo6 NPY-like immunoreactivity is found in PDD neuritic plaques.lo7 Neurotensin immunoreactivity is unaltered in several brain regions in PDD, but is increased in the frontal and temporal cortex of Down's patients. The latter changes appear related to the presence of plaques and tangles.108 Angiotensin-

36

Section I

- CNS Agents

Hesp, Ed.

I1 facilitates learning and retention in active avoidance paradigms in shuttle-box-trained rats when administered (i.c.v.) before or after training. Saralasin, while having no effects of its own, blocked the effects of angiotensin-I1 on 1earning.lo9 The peptide HPhe-Ile-Tyr-SerTyr-LysOH (36) reverses ECS-induced amnesia and facilitates Tdiscrimination task learning in rats.l1°

Nootropics and other agents - Most compounds described as nootropics are pyrrolidone derivatives, the first example being piracetam (37). Piracetam-treated dyslexic boys were faster readers, but no effects were observed on reading accuracy or comprehension, Piracetam improved auditory short-term memory in individuals with relatively poor memory,lll produced clinical improvement in some adult males with alcoholic psychosis and increased cerebral blood flow and somatosensory evoked potentials in hypotensive cats.l13 Peak serum concentrations are reached within one hour, and little metabolism occurs.l14 Specific combinations of piracetam and Ch enhanced habituation of exploratory activity in mice, but neither drug alone had an effect.l15 Piracetam-Ch combinations affect hippocampal rhythmic slow activity in rabbits.l16 Piracetam potentiates the anticonvulsant effects of carbamazepine.lI7

oGR:. I

R

43 -

37 R

= CH2CONH2, R' = R" = H R = C(CN)=CHNMe2, R' = R" = H R = CH2CONH2, R' = H, R" = OH R = CH2CONH(CH2)2N(iPr)2, R' = R" = H R = 4-MeOPhCO, R ' = R" = H 42 R = 4-MeOPhCO, R' = (CH2)2COOH, R" = H

38 39 40 41

44 -

45 -

Structure activity relationships were proposed for piracetam analogues that affect spontaneous locomotor activity, ECS-induced retrograde amnesia, and survival under hypoxic conditions.l18 Compound 38 is twice as active as piracetam in protecting mice against acute hypoxia.l19 Oxiracetam (ISF-2522, 2)was more effective than piracetam in improving neurological and somatic symptoms associated with chronic cerebrovascular insufficiency in elderly patients, possibly via platelet aggregation inhibition.120 Oxiracetam is excreted unchanged (>go%) in urine after oral administration.121 The synthesis and activities of a series of analogues o f pramiracetam (CI-879, 9) were described.122 Pramiracetam shows a "therapeutic window" in terms of effects on learned behavior, gross EEG activity of the hippocam us and frontal cortex, and firing rate of single hippocampal neurons.p23 Aniracetam (Ro-13-5057, 41) improved the accuracy of pigeons and monkeys o n variable-delay matchin -to-sample and antagonized scopolamine-induced impairment in monkeys.k24 The activity of tenilsetam (CAS-997, 43) in animal models of cognition was reviewed.125 Beneficial effects observed with CAS-997 may reflect positive actions on metabolic and cholinergic functions.126 The chemistry and pharmacology of CI-844 (g),lz7 rolziracetam (CI-911, were briefly reviewed. 45),128 and CI-933

Chap. 4

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-

Hershenson, Marriott, Moos 37

Pentoxifylline ( 4 6 ) , a PDE inhibitor, reverses age-related spatial m e m o r y deficits.130- Propentofylline (HWA 285, 47) reverses cycloheximide-induced amnesia in mice,131 and affects rat cerebral metabolism132 and human psychomotor performance, mood, and memory.133 Hoe 175 (48) enhances memory in mice.134 Pyritinol (49) facilitates (CVretention o f a learned task in poor learners only.l35 ?debenone 2619, 50) protects against cerebral ischemia-induced amnesia in rats.136 Sulfoxazlne (Y-8894, 51) protected mice against ECS-induced amnesia and hypoxia but had no effect on learning and memory.137 Buflomedil (52) was well tolerated in demented patients, and some improvement in cognitive function was noted.138

46 R-Me 47 R=Et -

48 -

49 -

M e O A O M e

OMe

51 -

50 -

52 -

While preclinical and preliminary clinical studies have often been encouraging with the newer cognition activators, well-designed, doubleblind, placebo-controlled trials have thus far failed to demonstrate unequivocal drug effects. References

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x,

s,

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E n g l . J. Med., 312, 7 2 5 (1985). 83. L. V e c s e i , I. B o l l o k , J. V a r g a , B. P enke a n d G. T e l e g d y , N e u r o p e p t i d e s , 4, 137 (1984). 84. A. S a h g a l, Psychopharmacology, 83, 215 (1984). 8 5 . R.E. T i l l a n d B.E. B e c k w i t h , P e p t i d e s , 6 , 397 ( 1 9 8 5 ) . 8 6 . B.E. B e c k w i t h , R.E. T i l l a n d V. S c h n e i d e r , P e p t i d e s , 5, 819 (1984). 8 7 . D. S t e i n , J. B a n n e t , I. A v e r b u c h , L. L a n d a , S. Cha z a n a n d R.H. B e l m a k e r , Psychopharmacology. 84, 566 (1984). 8 8 . G. E i s e n h o f e r , D.G. L ambl e and B . J . R o b i n s o n , L i f e S c i . , 2,2499 ( 1 9 8 5 ) . 89. A. Je n n e k e ns-S chi nkel , A.R. Wintzen and J.B.K. La ns e r, Prog. Neuro-Psychopharmacol. B i o l . P s y c h i a t r y . 2 , 2 7 3 (1985). 90. C.A. P e a b o d y, S. T h i e m a n n , R. P i g a c h e , T.P. M i l l e r , P.A. B e r g e r , J. Y e s a v a g e a n d J . R . T i n k l e n b e r g , Neurobiol. Aging, 6 , 95 (1985). 91. H. S o i n i n e n , T. K o s k i n e n , E.L. H e l k a l a , R. P i g a c h e a n d P.J. R i e k k i n e n , N e u r o l o g y , 3, 1348 (1985). 92. A.N. N i c h o l s o n , B . M . S t o n e a n d S.J. J o n e s , E U K . J. C l i n . P h a r m a c o l . , 27, 5 6 1 (1984). 93. S.O. F r e d e r i k s e n , C. d ' E l i a a n d B.O. B e n g t s s o n , A c t a P s y c h i a t r . Sc a nd. , 1_1. 3 4 1 (1985). 94. S.O. F r e d e r i k s e n , C. d ' E l i a a n d B.O. B e n g t s s o n , A c t a P s y c h i a t r . Sc a nd. , 1_1, 349 (1985). 95. F. F a c c h i n e t t i , G. N a p p i , F. P e t r a g l i a , E. M a r t i g n o n i , E. S i n f o r i a n i a n d A.R. G e n a z z a n i , L i f e S c i . , 2,1 6 9 1 (1984). 96. I.B. I n t r o i n i a n d C.M. B a r a t t i , Behav. N e u r a l . Biol. . 41. 1 5 2 (1984). 97. C.M. B a r a t t i , I . B . I n t r o i n i a n d L. Huygens, Behav. N e u r a l . B i o l . , 40,1 5 5 (1984). DeAlmeida and V.R. E m i l i a n o , Psychopharmacology, g , 216 98. I. I z q u i e r d o , M.A.M.R. (1985). 99. R. S u l k a v a , T. E r k i n j u n t t i and T. L a a t i k a i n e n , Neurology, 21, 1057 (1985). 1 0 0 . P. N. T a r i o t , T. S u n d e r l a n d , H. W e i n g a r t n e r , D.L. Murphy, M.R. Cohen a n d R.M. Cohe n, Psychopharmacol. Bull., 21, 680 (1985). 101. H.A. N a s r a l l a h . N. Varney, J.A. Coffman, J. Ba yle s s and S. Chapman, Psychopharmacol. Bull., 89 (1985). 102. G.G. Yarbrough and N. Pomara, Prog. Neuro-Psychopharmacol. Biol. P s y c h i a t r y , 2, 285 (1985). 1 0 3 . A . I . F a d d e n a n d T.P. J a c o b s , N e u r o l o g y , 3 5 , 1 3 3 1 ( 1 9 8 5 ) . 1 0 4 . T. K a d a r , 8. P e n k e , K. Kovacs a n d G. T e l e g d y , N e u r o p e p t i d e s , 4 , 1 2 7 ( 1 9 8 4 ) . 105. C. Wikkelso, J. Fahrenkrug, C. Blomstrand and B.B. J oha ns s on, Neurology, 21, 592 (1985). 1 0 6 . T.S. G r a y a n d J.E. M o r l e y , L i f e S c i . , 389 ( 1 9 8 6 ) . 107. I). D a u b a r n a n d P.C. E m s o n , Biochem. B i o p h y s . Res. Commun., 126,2 8 9 ( 1 9 8 5 ) . 1 0 8 . C.M. Y a t e s , G. F i n k , J . G . B e n n i e , A. G o r d o n , J. S i m p s o n a n d R.L. E s k a y , .I.N e u r o l . S c f . , 67, 327 (1985). 10 9 . V. G e o r g i e v a n d D. Yonkov, M e t h o d s F i n d . E x p t l . C l i n . P h a r m a c o l . , 1. 4 1 5 (1985). 11 0 . L. V e c s e i , I. B o l l o c k , G. T e l e g d y a n d A.V. S c h a l l y , E x p . B r a i n Res., 57, 6 2 5 ( 1 9 8 5 ) . 111. M. D i I a n n i , C.R. W i l s h e r , M.S. B l a n k , C.K. C o n n e r s , C.H. C h a s e , H.H. F u n k e n s t e i n , E. H e l f g o t t , J . M . Hol mes, L. L ougee, G.J. M a l e t t a . J. M i l e u s k i , F.J. P i r o z z o l o , R.G. Rude1 a n d P. T a l l a l , J . C l i n . P s y c h o p h a r m a c o l . , 5 , 2 7 2 ( 1 9 8 5 ) . 1 1 2 . V. S k o n d i a a n d J. K a b e s , J. I n t . Med. Res., 135 (1985). 113. M. S a t o a n d W.-D. Heiss, Arznei m. F o r s c h . , 3 5 , 790 ( 1 9 8 5 ) .

z,

a,

13,

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114. M.T. T a c c o n i a n d R.J. W urt man, J. Pharm. P h a r m a c o l . , E, 6 5 9 (1984). 115. A. P l a t e l , M. J a l f r e , C. P a w e l e c , S. Roux a n d R.D. P o r s o l t , P h a r m a c o l . Biochem. Behav., 21, 209 (1984). 1 1 6 . G. F o n t a n i , F. G r a z z i a n d M. M e u c c i , L i f e S c i . , 35, 1 1 8 3 (1984). 1 1 7 . C. M o n d a d o r i , M. S c h m u t z a n d V. B a l t z e r . Acta N e u r o l . Scand., 69, 131 (1984). 118. R.Ya. P o p o v a , T.A. G u d a s h e v a , S.S. T r o f i m o v , R.V. O s t r o v s k a y a a n d A.P. S k o l d i n o v , Khim. F a r m . Zh., 17,1 4 3 9 (1983). 1 1 9 . T.V. S t e z h k o , V.G. G r a n i k , R.G. G l u s h k o v , L.F. R o s h c h i n a , A.I. P o l e z h a e v a a n d M.D. M a s h k o v s k i i , Khim. Farm. Zh., g , 290 ( 1 9 8 4 ) . 1 2 0 . E. F e r r e r o , C u r r . T her. Res., 36, 2 9 8 (1984). 1 2 1 . E. P e r u c c a , A. A l b r i c i , G. G a t t i , R. S p a l l u t o , M . V i s c o n t i a n d A. C r e m a , Eur. J. D rug Metab. Pharmacokinet., 2, 267 (1984). 1 2 2 . D.E. B u t l e r , I . C . N o r d i n , Y . J . L ' I t a l i e n , L. Z w e i s l e r , P.H. P o s c h e l a n d J . G . M a r r i o t t . J. Med. Chem., 27, 6 8 4 ( 1 9 8 4 ) . 1 2 3 . B.P.H. P o s c h e l , P.M. Ho, F.W. N i n e t m a n a n d M.J. C a l l a h a n , E x p e r i e n t i a , 5, 1153 (1985). 1 2 4 . M . J . P o n t e c o r v o a n d H.L. E v a n s , P h a r m a c o l . Biochem. Behav., 22, 7 4 5 (1985). 125. U. S c h n i d l e r , D.K. Rush a n d S . F i e l d i n g , Drug Dev. Res., 5, 567 ( 1 9 8 4 ) . 126. U. S c h i n d l e r , R. B e v e r l e and R.E. N i t z , Naunyn-Schmiedeberg's Arch. Pharmacol., 3 3 0 ( 1 9 8 5 ). 127. D r u g s F u t u r e , lo,279 (1985). 1 2 8 . D r u g s F u t u r e , lo,988 ( 1 9 8 5 ) . 129. D r u g s F u t u r e , lo,972 (1985). 1 3 0 . L. d e T o l e d o - M o r r e l 1 , F. M o r r e l l , S. F l e m i n g a n d M.M. Cohen, Behav. N e u r a l . B i o l . , 4 2 , 1 ( 1 9 84). 131. K G o t o , N. Demura and T. S a k a g u c h i , J. P h a r m a c o b i o d y n . , S , s - 7 3 (1985). 132. V. S t e f a n o v i c h , Drug Dev. Res., 327 (1985). 133. I. H i n d m a r c h a n d 2. S ubhan. Drug Dev. Res., 5, 3 7 9 (1985). 134. F.J. Hock and J.L. McGaugh, Psychopharmacology, E, 114 (1985). 135. L. V a l t e l l i a n d S. T o m a s i k o v a . M e t h o d s F ind. E x p t l . C l i n . P h a r m a c o l . , 1. 5 1 5 (1985). 349 ( 1 9 8 4 ) . 1 3 6 . N. Y a m a z a k i , Y. T a k e , A. Nagaoka and Y. Nagawa, J p n . J. P h a r m a c o l . , 137. K. Anami. Y. Yamamoto and M. S et oguchi . Nippon Yakurigaku Z a s s h i , E, 7 1 (1985). 138. B. L e v i n s o n , P. W r i g h t a n d S. B a r k l e m , S . A f r . Med. J., 68, 302 (1985).

a,

a,

Chapter 5. Drugs Acting at Central 5-Hydroxytryptamine Receptors Derek N. Middlemiss Continental Pharma, 11 rue Grandbonpr;, B-1348 Mont-Saint-Guibert, Belgium Marcel Hibert and John R. Fozard Merrell Dow Research Institute, Strasbourg Center, 16 rue d'hnkara F-67084 Strasbourg Cedex, France Introduction - Since the last review on central 5-hydroxytryptamine (5-HT, serotonin) receptors appeared in this series, major advances have been made in the definition of the functional consequences of he stimulation F: and blockade of these multiple receptor sites in the CNS. To a large degree, these advances have been made possible by the availability of drugs, both agonists and antagonists, with a degree of selectivity and activity at the various central 5-HT receptor subtypes. The purpose of this review i s to identify the key drugs which have led to these advances and to give an indication of their potency and selectivity at central 5-HT receptors. Central 5-HT r ceptors have been the subject of several recent 1-5 reviews and monographs. Important advances have also been made in the identification of compounds with effects at peripheral 5-HT re e tors and $P the reader is referred to a series of reviews on this subject. Central 5-HT receptor classification - On the basis of radioligand binding studies, central 5-HT recognition sites wer;e originally classified into 1u two subtypes, designated 51HT and 5-HT It is now generally accepted that the 5-HJ recognition sik,, define2 on the basis of high affinity binding of [ A]-spiperone or [ H]-ketansfiin, has many functional correlates in the CNS and the peripheryj Correlates o f the 5-HT 1 recognition site, which is labeled by [ H]-5-HT, have proven more difficult to determine and indeed the relati n ip of these binding sites Over the last few years, to functional receptors has been questioned. however, it has become increasingly evident that the original definition of the 5-HT site as a single homogeneous entity was an oversimplification an& that at least three subtygtB3may exist. These have been designated 5-HTlA, 5-HT1 and 5-HT Extensive autoradiographic 1c' studies of the regio of central 5-HT recognition sites have been published.

.

a,sP

Pttl!istribution

5-HT

Recognition sites - A number of compounds shows selective affinity for f-HT as compared to 5-HT recognition sites. T se include the 1 putative agonists, 5-carbamoyitryptamine (5-CT, A ) , 1j-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl]pdole (RU 24969, 2), 1-(3-acetamidopheny1)piperazine (BEA 1654, 3 ) and seYerqt, putative antagonists such as propranolol, pindolol and cyanopindolol. In general, the abovementioned drugs have similar affinities for both the 5-HT and 5-HTlB subtypes of the 5-HT1 recppition site, and cannot be use!lAas tools to distinguish between them.

9%

5-HT Recognition sites : identification and functional 1A functional effects of stimulation of the putative 5-HT

1A

ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21

correlates - The receptor have

Copyright 0 1986 byAcademic Press,Ine. All rights of reproduction in any form reserved.

42

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received considerable attention over the last 3 years. Of crucial importance to these studies was the finding that the tetralin derivati'25 , receptor. 8-OH-DPAT (?), is a selective agonist at the putative 5-HT &A600 times more In radioligand binding studies this compound proved t Tritiated f! has or 5-HT sites.q6'57 potent at 5-HT sites than at 5-HT 2 1A is now used to lake1 B selectively been gfjepared and the 5-HTIA recognition Compound 4 has many central and peripheral actions ins4uding site. effects ogOthe cardiovascula51system, feeding behavi95, sexual activity, he startle response and body temperature .35 Attempts have Nfi been made to confirm the receptor type involved in the functional responses to 8-OH-DPAT. For example, the potent stimulant effect on adenylate -4 cyclase activity in guinea pig hippocampus homogenates is blocked by spiperone, a potent 5-HT receptor antagonist which 2 has 5-HT receptor antagonist activity, but not by the more selective 1A 5-HT receptor antagonist, ketanserin, nor by the 5-HT receptor y p g onis$, luH, 3u, 5aH-tropan-3-yl-3,5-dichlorobenzoate (dDL 72222). Electrophysiological studies in the rat dorsal hippocampal slice preparation indicate that the decreases in the CA1 population spike amplitude, 35 induced by 5-HT or a-OH-DPAT, are also mediated by the 5-HT receptor. Contraction of the canine basilar artery inducjgd by 8-OH-DPAt appears similarly to be mediated by 5-HT1 receptors. These in vitro studies are complemented by in vivo experiments which demonstrate that certain of the ion of behavioral effects of 8-OH-DPAT are the result of the sti 5-HT A receptors, as are its effects on body temperature. inhihition of transmitter release following field stimulation of the recognition site guinea pig ileum & a functional correlate of the 5-HT 1A in the periphery.

5-HTIA Recognition

sites : new ligands - Compounds with appreciable affinity for the 5-HT recognition site can be classified under the 1A fo 1 lowing headings :

Tetralin derivatives - Compound 4 was of particular interest in that its tetralin structure was chemically distinct from earlier classes of 5-HT receptor agonists. The position of the hydroxy substituent is crucial for the potency and selectivity of the compound at the 5-HT site. Thus, whereas 4 has no effect on central catecholamine receptors,'$-, 6- or 7-h rox lated derivatives have powerful dopamine receptor agonist activix j Many other tetralin analogues have been prepared and tested for acty. tivitx2at central 5-HT receptors using biochemical and behavioral tests in rats. Quantification of this activity by measuring changes in 5-HTP turnover in limbic structures, striatum and cortex allowed the following conclusions: (i) 0-methylation of 4 results in a 6-fold decrease in activity; (ii) modification of the amino substituent gives the order of potency -NH-nBu < -NH-iPr 6000a > 5000;

25 185 280

3 50 115 480

-

-

620 315 250

145 25

35 25

65 > 2500

70 565

> 1800

18

> 1800

0.3

-

-

1300 3900

110 135

110 1300

8

> 440

65

35

8

-

-

-

-

-

60 5800

280

34

260000

> 3000 > 2500; > 2500

200 125 75

-

-

Butyrophenone Derivatives 8,82 Spiperone Pipampe ron 82 52 Benpe r ido1

0.53 0.78 1.20

190

-

-

-

-

Ergoline Derivatives 80 2-iodo-LSD Metergoline 8’82 Methyaeg9ide 82 d-LSD ’ Me sulerg&ye Me -I-LSD LY 53587 O1

0.9 0.28 0.94 2.50 3.16b 0.26b 0.05

35a 46

-

180 No effect

-

-

-

-

44 80

-

-

Tricyclic Derivatives 82 Pizot ifen 82 Clopipazan Methiothepine8’82 Cyproheptgt&ge 82 Mianse rin

0.28 0.39 0.39

-

-

-

-

-

-

-

95

14

1

80

0.44 1.4

-

-

-

-

710

2.0

58

43

10 442

-

-

-

-

-

-

-

Miscellaneous 82 C1ozapine 82 Xylamidine 82 Cinanserin

2.6 1.5 2.0

-

-

-

a: Selectivity versus the high affinity 5-HT1 site. b: Dissociation constant

-

-

-

19

Ergoline derivatives - The classical 5-HT receptor antagonists, LSD, methysergide and metergoline have been joined recently by several new highlgoactive compounds containinggshe ergoline skelet -iodo-LSD (30) , N -methyl-2-iodo-LSD ( 2 1 , rnesulergine (31)’99’i0’ and LY 53857 (Z). A11 lo these 1 compounds show a degree of selectivity €or the 5-HT2 site. LY 53857, which lacks al-adrenoceptor and dopamine receptor antagonist activities, sQ8y385tivity in animal models predictive of antidepressant activity.

48 -

Section I

x

30

31 32 33 -

- CNS Agents R,

Hesp, Ed.

a

Rl

1

H

1

MO CONE12

CONEt,

H

MI

NHSO~NMI,

HH

H

,.Pr

CO,CH(Mo)CHOKCH,

HH

Miscellaneous - Diverse chemical structures have been reported to have 5-HT receptor antagonist properties. For example, 1-( 1-naphthy?)-piperazine (34) shows good affinity for the 5-HT2 receptor and, beinglatme 2000 times less active at al-adrenoceptors, is maftf3dly selective. Ty&,other aryl piperazine derivatives, TR 2515 ( 2 ) and trazodone are also 5-HT receptor antagonists. The benzazepine 2 (SCH 2 3 3 9 0 ) , which is a dopamine D -receptor antagonist, {@ibits 1 [ HI-spiperone binding in rat cortex with an IC o f 1 1 2 nM. 50 o f 290 nM in the V e r a p a m i l , l ~ 8 c \ ~I1 ~ s calcium-antagonist, had an IC same test. Two related amidines, xylamidine 8 ) and BW 501C67 (E),display high affinity for the 5-HT2 receptor."BW 501C67 discriminates effectively between 5-HT2 and a -adrenoceptors 1 1BP:lfSL remarkable in being unable to block central 5-HT 2 receptors*

(s),

3

Re f e r e n c e s

1. J . E . Leysen a n d J.P. T o l l e n a e r e , Annu. Rep. Med. Chem., 11, 1 ( 1 9 8 2 ) . 2 . B.L. J a c o b s a n d A. C e l p e r i n , S e r o t o n i n N e u r o t r a n s m i s s i o n and B e h a v i o u r , MIT P r e s s , Cambridge, M a s s a c h u s e t t s , 1981. 3. B. Haker. S . Cabay, M.R. I s s i d o r i d e s a n d S.C.A. A l i v i s a t o s . S e r o t o n i n : C u r r e n t A s p e c t s o f N e u r o c h e m i s t r y a n d F u n c t i o n , Plenum P r e s s , New York, N.Y. 1981. 4. D . N . Middlemiss i n " P r e s y n a p t i c R e c e p t o r s : Mechanisms a n d F u n c t i o n s " , J. d e B e l l e r o c h e , 1982, p 46. Ed., E l l i s Horwood, C h i c h e s c e r , U.K.. 5. R.W. F u l l e r , Monogr. N e u r a l S c i . , lo, 1 5 8 ( 1 9 8 4 ) . 6. N . N . O s b o r n e , B i o l o g y of S e r o t o n e r g i c T r a n s m i s s i o n , J o h n Wiley a n d Sons, 1982. C h i c h e s t e r , U.K., 7. B . T . Ho, J.C. S c h o o l e r a n d E. U s d i n , Adv. Biochem. P s y c h o p h a r m a c o l . , 34, 1 (1982). 8. A . R . G r e e n , Neuropharmacology of S e r o t o n i n , Oxford U n i v e r s i t y Press, Oxford. U.K., 1985.

9. 10. 11. 12. 13.

14. 15. 16.

17.

23,

P.B.

Bradley, Neuropharmacol., 1465 ( 1 9 8 4 ) . S . J . P e r o u t k a a n d S.H. S n y d e r , Mot. Pharrnacol.. 1 6 , 687 ( 1 9 7 9 ) . J . R . F o z a r d , T r e n d s Pharmacol. S c i . , 288 ( 1 9 8 5 . N.W. P e d i g o , H . I . Yamarnura and D.L. N e l s o n , J. Neurochem., 2 2 2 (1981). A. P a z o s , D. Hoyer a n d J.M. P a l a c i o s , Eur. J. P h a r m a c o l . , 539 ( 1 9 8 5 ) . A. Pazos a n d J.M. P a l a c i o s , B r a i n R e s . , 346, 205 ( 1 9 8 5 ) . A. P a z o s , 1. C o r t e s a n d J . M . P a l a c i o s , B r a i n Res., 346, 231 ( 1 9 8 5 ) . C. E n g e l , M. G o t h e r t , D. Hoyer, E. S c h l i c k e r a n d K. H i l l e n b r a n d , Naunyn-Schrniedeberg's 1 (1986). Arch. Pharrnacol., M.D. T r i c k l e b a n k , D . N . Middlemiss and J . N e i l l , Neuropharrnacol., in p r e s s ( 1 9 8 6 ) .

5,

332,

2, 106,

Chap. 5

Central 5-HT Receptors

Middlemiss, Hibert, Fozzard

9

1 8 . P . D . Verdouw, H . M . J e n n e w e i n , J . Mierau and P.R. S a x e n a , Eur. J . P h a r m a c o l . , 107, 337 1985). 19. S.R. Nahorski and A.L. W i l l c o c k s , Br. J. P h a r m a c o l . , 78, 1071 ( 1 9 8 3 ) . 20. D.N. M i d d l e m i s s , Eur. J . P h a r m a c o l . , 101, 289 ( 1 9 8 4 ) . 21. D. Hoyer, G . Engel and H . O . Kalkman, Eur. J . P h a r m a c o l . , G, 1 ( 1 9 8 5 ) . 1143 ( 1 9 8 5 ) . 22. S . H j o r t h a n d A. C a r l s s o n , Neuropharmacol., 3, 23. D . N . M i d d l e m i s s , Eur. J. P h a r m a c o l . , 120, 51 ( 1 9 8 6 ) . 24. E . S c h l i c k e r , M. G o t h e r t and K . H i l l e n b r a n d , Naunyn-Schmiedeberg's Arch. P h a r m a c o l . , 331, 398 ( 1 9 8 5 ) . A r v i d s s o n , U. 25. S . H j o r t h , A. C a r l s s o n , P. L i n d b e r g , D. S a n c h e z , H . Wikstrom, L . - E . H a c k s e l l a n d J.L.G. N i l s s o n , J . N e u r a l T r a n s m i s s i o n , 2 , 169 ( 1 9 8 2 ) . 26. D . N . Middlemiss and J . R . F o z a r d , E u r . J. P h a r m a c o l . , 90, 151 ( 1 9 8 3 ) . 21. M. Hamon, S. B o u r g o i n , H. G o z l a n , M.D. H a l l , C. G o e t z , F. A r t a u d and A.S. Horn, E u r . J . Pharrnacol., 100, 263 ( 1 9 8 4 ) . 28. H . G o z l a n , S . E l Mestikawy, L. P i c h a t , J . G l o w i n s k i and M. Hamon, N a t u r e , 305, 140 ( 1983). 305 29. K. G r a d i n , A. P e t t e r s s o n , T. Hadner and B. P e r s s o n , J . Neural T r a n s m i s s i o n , 1985). 30. C . T . D o u r i s h , P . H . Hutson a n d G . Curzon, P s y c h o p h a r m a c o l . , 9, 197 ( 1 9 8 5 ) . 31. S . A h l e n i u s , K. L a r s s o n , L. S v e n s s o n , S . H j o r c h , A. C a r l s s o n , P. L i n d b e r g , H . Wikstrorn, D. S a n c h e z , L.-E. A r v i d s s o n , 0. H a c k s e l l and J . L . G . N i l s s o n , Pharmacol. Biochem. Behav., 15, 7 8 5 ( 1 9 8 1 ) . 32. L. Svensson a n d S. A h l e n i u s , Psychopharmac., 2. 1 0 4 ( 1 9 8 3 ) . 33. S. H j o r t h , J. N e u r a l T r a n s m i s s i o n , 61, 131 ( 1 9 8 5 ) . 427 34. A. S h e n k e r , S. Maayani, H. W e i n s t e i n and J . P . G r e e n , Eur. J . Pharmacol., (1985). 35. S.G. Beck, W.P. C l a r k e and J . G o l d f a r b , Eur. J . P h a r m a c o l . , 116, 1 9 5 ( 1 9 8 5 ) . 36. E . W . T a y l o r , S.P. Duckles and D . L . N e l s o n , J. Pharmacol. Exp. T h e r . , 236, 1 1 8 ( 1 9 8 6 ) . 37. M.D. T r i c k l e b a n k , C . F o r l e r and J . R . F o z a r d , E u r . J . P h a r m a c o l . , 106, 271 ( 1 9 8 4 ) . 38. D . N . M i d d l e m i s s , J . N e i l 1 and M.D. T r i c k l e b a n k , Br. J . Pharmacol., g , 251P ( 1 9 8 5 ) . 39. M.D. T r i c k l e b a n k , C. F o r l e r , D . N . Middlerniss a n d J.R. F o z a r d , Eur. J . P h a r m a c o l . , 1 5 (1985). 40. J.R. Fozard and H . K i l b i n g e r , Br. J . P h a r m a c o l . , 86, 6 0 l P ( 1 9 8 5 ) . 41. L.-E. A r v i d s s o n , U. H a c k s e l l , J.L.G. N i l s s o n , S . H j o r t h , A. C a r l s s o n , P. L i n d b e r g , D. Sanchez and H . W i k s t r h , J . Med. Chem., 921 ( 1 9 8 1 ) . 42. L.-E. A r v i d s s o n , U. H a c k s e l l , A.M. J o h a n s s o n , J . L . G . N i l s s o n , P . L i n d b e r g , D. S a n c h e z , H. Wikstrom, K. S v e n s s o n , S. H j o r t h a n d A. C a r l s s o n , J . Med. Chem., 45 (1984). 43. A. Hagenbach, D. Hoyer, H . O . Kalkman and M.P. S e i l e r , Br. J . P h a r m a c o l . , i n p r e s s (1986). 44. H . W . Wikstrom, D. S a n c h e z , P. L i n d b e r g , L.-E. A r v i d s s o n , U . H a c k s e l l , A. J o h a n s s o n , J.L.G. N i l s s o n , S . H j o r t h a n d A. C a r l s s o n , J . Med. Chem. 5. 925 ( 1 9 8 2 ) . 45. L.-E. A r v i d s s o n , D o c t o r a l t h e s i s , Uppsala U n i v e r s i t y , ISBN 91-554-1720-5, Uppsala, 1985. 46. M.B. E m e r i t , H . G o z l a n , M.D.Hal1, M . Harnon and A . Marquee, Biochem. P h a r m a c o l . , 34, 883 ( 1 9 8 5 ) . 47 * J . R . Fozard a n d I . McDermott, Br. J . Pharmacol., &, 69P ( 1 9 8 5 ) . 48. P . H u n t , C. O b e r l a n d e r , Adv. Exp. Med. B i o c h . , 133, 547 ( 1 9 8 1 ) . 49. D.N. Middlemiss. J . Pharm. Pharmacol., 2,4 3 4 ( 1 9 8 5 ) . 50. C . E u v r a r d and J . B o i s s i e r , Eur. J . P h a r m a c o l . , 63, 6 5 ( 1 9 8 0 ) . 51. M.H. S m i t , R.L. G l e n n o n , H . I . Yamamura a n d D.L. N e l s o n , S o c i e t y f o r N e u r o s c i e n c e : 1 1 t h m e e t i n g , Los A n g e l e s , Ca, 1981. 52. E.W. T a y l o r and D.L. N e l s o n , ASPET M e e t i n g , B o s t o n , Mass, Aug. 1 9 8 5 . 53. D . L . Temple, J r , J . P . Yevich and J . S . New, J . C l i n . P s y c h i a t r y , 43, 4 ( 1 9 8 2 ) . 54. P . L . Wood, N.P.V. N a i r , S . La1 and P . E t i e n n e , L i f e S c i . , 2 , 2 6 8 ( 1 9 8 3 ) . 55. S. H j o r t h and A. C a r l s s o n . , Eur. J . P h a r m a c o l . , 83, 299 ( 1 9 8 2 ) . 56. T . G l a s e r a n d J . T r a b e r , Eur. J. P h a r m a c o l , 88, 137 ( 1 9 8 3 ) . 5 1 . S.J. P e r o u t k a , B i o l . P s y c h i a t r y , 0 , 971 (1985). 255 ( 1 9 8 3 ) . 5 8 . B.A. McMillen and L.A. M a t t i a c e , J . Neural T r a n s m i s s i o n , 59. F.D. Yocca and S. Maayani, ASPET M e e t i n g , B o s t o n , Mass., Aug. 1985. 6 0 . J . P . Yevich, D.L. Temple, J r . , J . S . New, D . P . T a y l o r and L.A. R i b l e t , J . Med. Chem., 26, 1 9 4 ( 1 9 8 3 ) . 61. J . T r a b e r , M.A. D a v i e s , W . U. Dompert, T. G l a s e r , T. Schuurman a n d R.P. S e i d e l , B r a i n Res. B u l l . , g,741 ( 1 9 8 4 ) . 6 2 . W.U. Dompert, T . G l a s e r a n d J . T r a b e r , Naunyn-Schmiedeberg's Arch. P h a r m a c o l . , 328, 467 ( 1 9 8 5 ) . 63. K.B. A s a r c h , R.W. Ransom and J . C . S h i h , L i f e S c i . , 2,1 2 6 5 ( 1 9 8 5 ) . 68 (1986). 66. R.W. Ransom, K . B . Asarch and J . S h i h , J . Neurochem., 875 ( 1 9 8 5 ) . 6 5 . R.W. Ransom, K.B. A s a r c h a n d J . C . S h i h , J . Neurochem., 461 66. A.B. Norman, G . B a t t a g l i a , A.L. Morrow a n d I . C r e e s e , Eur. J . P h a r m a c o l . . (1985). 6 1 . M.A. S i l l s , B.B. Wolfe a n d A. F r a z e r , J . Pharmacol. Exp. T h e r . , 231, 4 8 0 ( 1 9 8 4 ) . 68 D . Hoyer, G. Engel and H . O . Kalkman, Eur. J. P h a r m a c o l . , 118, 13 ( 1 9 8 5 ) . 69. D.N. M i d d l e m i s s , Naunyn-Schmiedeberg's Arch. P h a r m a c o l . , 327, 18 ( 1 9 8 4 ) .

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2.


1 pM.25 This dramatic difference in renin inhibitory potency is apparently due to the binding of 12 t o plasma proteins. The fluoro statinone derivative 12 exhibited enhanced potency over the desfluoro analog.26 Replacement of statine with (3S,4S )-4-amino-5cyclohexyl-3-hydroxypentanoic acid has yielded even more potent renin inhibitors.27 One of these compounds, 14, is 55-76 times as potent as the comparable statine containing compound against human renin & vitro and 19 times as potent in lowering pressure in Na+-deficient dog? A-60956 (151, an additional substrate analog, has a similar renin inhibitory profile & vitro.28 A new series of renin inhibitors incorporated an amino alcohol function as a non-hydrolyzable substitute for the scissile bond of angioten~inogen.~~ Compound 16 is the most active of these compounds and is much less potent against hog kidney than human plasma renin (IC50 1200 versus 3.5 nM). It is virtually inactive against pepsin or cathepsin D.

s)23

Pepstatin was ori inally derived from actinomycetes and contains two statine residues.38 Pepstatin A (17) lacks the affinity and specificity for human renin to be a usefx therapeutic agent, however, substitution of the -Val-Val- constituents of pepstatin with other amino acids, e.g. Phe-Nle, has yielded markedly more potent agents.31 SR42128 (g) shows lesser species specificity for renin inhibition (IC5os for man, rat and dogs: 2.8~10-~M, 6x10m7M and 4.8~10'~M, respectively). Compound 18, 1-10 mgfkg, i.v., produced a dose-related decrease in arterial pressure in Na+-deplete monkeys with a duration of action >3 hours, suggesting that inhibitors with 2 statine residues are more resistant to proteolytic cleavage.31 The deduction of the preprorenin precursor of human renin from the structural gene coding for human renal renin32 has led to the synthesis and testing of a number of incomplete segments (prosegments).33 Analogous to previous studies which have shown that prosegments of mouse submaxillary renin inhibited the intact enzyme,34 a number of peptide llprosegments" (e.g. 19) inhibited human plasma renin, especially those A number of other approaches including the NH2-terminal portion.33 to the discoveryfdesign of renin inhibitors have been reported. Compound 20, 3 mgfkg, i.v., demonstrated a brief (t20 min) hypotensive effect in Na+-deficient rhesus monkeys.35 Compound 2 l , a "dipeptide glycol", 10 mglkg, i.v., briefly lowered PRA in rhesus monkeys.36

ACE Inhibitors - The chemistry and pharmacology of ACE1 have been reviewed.'Recent clinical developments include a long-term multicenter surveillance sudy of captopril ( 2 2 Po and examination of The captopril analog enalapril (23) in patients with heart failure? 24 (MC-838)-in normal volunteers reduced blood pressure with a longer duration of action than 22.42 The mercaptoaroyl compound 2 was ten

66

Section I1

- Pharmacodynamic Agents

Bristol, Ed.

times less potent in vitro than 22, yet was orally active in spontaneously hypertensive rats (SHR).= Benzazepin-2-one 26 exhibited a similar biological profile compared to 3 in the dogand 27 (CGS 14824A) paralleled 23 in the SHR.45 The benzothiazine 3 was equally potent to 27 when com ared i.v. in the SHR, but was less efficacious when administered orally.4g The oral potency of 2 was similar to 23 in the dog.47 The replacement of the amino moiety of CI-906 (30) with an oxygen atom provided 2, which showed modest oral antihypertensive

22 R = H

22

Rl R=

2,5

COOH

Mo

2J

t..

t!

(CH&NH2 Ph Ph

5

R2

CH2 Et CHZ Ct S H

activity in the renal hypertensive rat.48 Acyl tripeptide analogues of enalaprilat were reported. Since 21 and 3 furnished in vitro inhibitory potencies equal to enalaprilat, the extended peptide chains are not contributors to additional binding interactions.49 Pentapeptides 34 and 25 were approximately 30-40 times more potent than 2 in vitro b z

c 3

X=NH,R=N

-

k.

EtWC

'?

L o

COOH

2-9

7 COOH

j,2

COOH

31

X=NH,R=N

a

X=NH.R=N

X=O.R=N

A m

R= BzI

-

33

R='T H

Ph

COOH

did not lower blood pressure in renal hypertensive rats.50,51 A tritiated derivative of 34 revealed that 70% of an oral dose was absorbed and rapidly excreted unchanged from the blood with a half life of 24 Compound 2f! (R=H) was a potent in vitro ACEI, and although its prodrug 2 (R=Et) inhibited the ANG I response in normotensive rats when administered i.v. it displayed no oral efficacy.52 A carboxyethylcarbamoyl derivative 21. (R=H) was comparable to 22 in vitro and the ester 37 (R=Et) similiarly lowered blood pressure in the SHR when administered 0rally.5~ The fluoro ketone group in increased ACE inhibition & I vitro by 300-fold over methyl ketone 39.54 The utilization of

-

phosphonamidates as tetrahedral species furnished 40 (R=OPh Nonenzymatic hydrolysis of the phenyl ester gave 40 (R=OH) which was a potent in vitro ACEI. Phosphonamidate 5 was several orders of magnitude

Chap. 7

Antihypertensive Agents

Smith, Regan

67

less potent against ACE compared with enalaprilat .56 Evaluation of fermentation-derived molecules as ACEI revealed phenacein 4257 and a n ~ o v e n i nwith ~ ~ in vitro potencies of approximately ten and 150-foldY The interruption of the RAS utilizing respectively, less than 22. bradykinin-derived substrates furnished the des-Pro derivative Arg-Pro-Gly-Phe-Ser-Pro-Phe-Arg which was seven times more potent & vitro than 2 2 against ACE.)59 A bradykinin potentiating peptide '(BPp5,) anal 3500).92 of prazosin: compounds 54 (SM2470)g1 ACC-7513 (56) had twenty t G e s more affinit f o r a-receptors than for 5-HT-receptors in rabbit aortic strips. 94 Dual blocking activity ( a/81 = 1) was shown for 57.94 Compound 5 8 , an analog of the a 2-adrenoceptor antagonist RX 781094 (59 -),95 lg6-was eight times more

'1" 2

Chap. 7

Antihypertensive Agents

Smith, Regan

2

-7 ‘OM.

/‘I

@

o 750 pM f o r prostaglandin synthetase) .66 The synthesis o f the methylenec clopropane analog (23) has been reported, b u t no data were disclosed.6y The cyclopropyl compound 24 (TEI-8005) i n h i b i t s both 5-LO and 12-LO i n t h e 10-50 pM range.68 A s e r i e s o f mono-, d i - , and triethanoarachidonic acids f a i l e d t o i n h i b i t LTC4 and LTD4 production i n c a t lung t i s s u e , although 7.13-di ethanoarachidonic a c i d (25) sign1 f i c a n t l y i n h i b i t e d LTD4-induced c a t coronary a r t e r y c o n s t r i c t i o n (43% i n h i b i t i o n a t 5 pM1.69

A v a r i e t y o f s t r u c t u r a l l y diverse 5-lipoxygenase i n h i b i t o r s has been reported. SK&F 86002 (26) i s an o r a l l y a c t i v e dual 5-lipoxygenasel cyclooxygenase (CO) i n h i b i t o r (IC50 = 7.5 pM a.5-LO from RBL-1 c e l l s ) , and has potent anti-inflammatory e f f e c t s i n animal models g e n e r a l l y i n s e n s i t i v e t o CO i n h i b i t o r s (ED50 = 50 mg/kg, .o. i n arachi doni c a c i d-i nduced edema in mouse ear and r a t paw). 70 Another compound, L-652,343 (271, i n h i b i t s l e u k o t r i e n e and prostanoid synthesis a t sub-micromolar l e v e l s (IC50 = 0.5 pM f o r ram seminal v e s i c l e CO; IC50 = 2 pM E. 5-LO from RBL-1 c e l l s ) . The s t r u c t u r a l requirements f o r t h e observed a c t i v i t y o f 27 have been described. The 5-LO a c t i v i t y r e s u l t s p r i m a r i l y from the 3-hydroxybenzothiophene substructure, whereas the enamide side chain i s necessary f o r potent CO i n h i b i t i o n . 7 1 The a n t i - o x i d a n t t r i h y d r o x y i s o f l a v a n 28 e x h i b i t s potent i n h i b i t i o n o f human PMNL 5-LO (IC50 = 1.2 pM) w i t h s i g n i f i c a n t l y l e s s a c t i v i t against CO (IC50 = 200 pM) and human p l a t e l e t 12-LO (IC50 = 22 pM). 7s Diphenyl d i s u l f i d e r e v e r s i b l y i n h i b i t s RBL-1 5-LO a t 1-5 pM.73 i s a potent and s p e c i f i c i n h i b i t o r of RBL-1 5-LO and 12-LO Gossypol enzymes ( I C ~ Q= 0.3 pM and 0.7 pM, r e s p e c t i v e l ~ ) . ~A ~novel s e l eno-organ1 c compound, ebsel en (3,PZ-51). i n h i b i t s the production of 5-HETE and LTB4 by stimulated r a t PMNL c e l l s . 7 5 Several s t i lbenes i s o l a t e d from t h e r o o t s o f Polvqonum species, p l a n t s which have been used f o r t h e treatment of a l l e r g i c and inflammatory diseases, i n h i b i t r a t PMNL 5-LO and CO enzymes a t sub-micromolar concentrations .76

(a)

"op-q(oH CHO OH

HO

CHO

OH

HO

29

m

;

30

h

78

Section I1

- Pharrnacodynarnic Agents

Bristol, Ed.

-

PHOSPHOLIPASES I n c o n t r a s t t o e a r l i e r reports, D-dihexanoylphosphatidylc h o l i n e was found t o be a p a r t i a l competitive i n h i b i t o r o f t h e PLA2 h y d r o l y s i s o f t h e L-isomer.77 Human p l a t e l e t PLA i s i n h i b i t e d by a number o f unsaturated f a t t y acids, i n c l u d i n g palm t o l e l c , o l e i c , l i n o l e i c , l i n o l e n i c , and arachidonic, w i t h IC5os o f m. 0.5 pM. This i n h i b i t i o n i s apparently noncompetitive.78 This enzyme i s a l s o i n h i b i t e d by 5-, 12-, and 15-HETE, w i t h IC50 values o f 42, 26, and 72pM, respectively.79 The marine n a t u r a l product manoalide is a potent PLA2 i n h i b i t o r , i r r e v e r s i b l y r e a c t i n g w i t h l y s i n e residues.80 The i n h i b i t pancreati c fungal metabol it e s p l a s t a t i n (32) and l u t e o s p o r i n (3) PLA2 w i t h K i values o f 0.89 and 12.8 pM, respectively.81,82

P

(a)

The a n t i - m a l a r i a l drugs chloroquine and mepacrine, a t 10-100 pM, i n h i b i t 1e u k o t r i ene r e 1ease from unsensi t i z e d human 1ung and s e n s i t i z e d guinea p i g lung. These e f f e c t s a r e countered by t h e presence o f arachidonate, suggesting an e f f e c t on PLA2.83 Mepacrine a l s o i n h i b i t s ischemia-induced PLA2 a c t i v a t i o n i n porcine myocardium.84 The 11poxygenase/cycl ooxygenase inhi b i t o r s n o r d i hydroguai a r e t i c a c i d , 5,8,11 ,14-eicosatetraynoic acid, and quercetin i n h i b i t PLA2 a c t i v i t y o f neutro h i 1 e x t r a c t s and sonicates, w i t h IC50s i n t h e 10-100 pM range.15 The non-steroidal anti-inflammatory drug tiaramide (3) i n h i b i t s r a b b i t p l a t e l e t aggregation induced by collagen, b u t n o t by arachidonate.86 Patents claiming PLA2 i n h i b i t o r y a c t i v i t y f o r compounds such as 3587 and 3 8 8 have appeared. S t r u c t u r a l l y undefined PLA2 inhi b i t o r y f a c t o r s have been l o c a t e d i n bovine plasma89 and human amniotic f l u i d . 9 0 0

31

34 -

HO

3 2 , X=NH2, Y = OH 3 3 , X = V = OH -

35 -

36 -

A review a r t i c l e describes t h e PLAp-inhibitory a c t i o n o f t h e g l u c o c o r t i c o i d s . ~ l These s t e r o i d s e x e r t the1 r anti-inflammatory a c t i o n v i a t h e production o f macrocortin ( l i p o c o r t i n ) , an endogenous i n h i b i t o r o f PLA2. I n r a t p e r i t o n e a l 1eukocytes , both h y d r o c o r t i sone and macroc o r t i n i n h i b i t t h e release o f t h e PAF precursor, 2-lyso-PAF. This i n h i b i t i o n could comprise an important corn anent o f t h e i r a n t i anaphylactic and anti-inflammatory action.!Z Dexamethasone i n h i b i t s carrageenin-induced edema i n the r a t paw, a standard model o f experimental inflammation t h a t i n v o l v e s arachidonate metabolites. To a l e s s e r extent, t h i s s t e r o i d a l s o i n h i b i t s dextran-induced edema (mediated l a r g e l y by histamine and 5-hydroxytry tamine), apparently through t h e generation o f o t h e r r e g u l a t o r y p r o t e i n s . I 3 Dexamethasone a l s o has a d i r e c t e f f e c t on snake venom PLA2, manifesting i t s i n h i b i t i o n w i t h i n 3-10 minutes.94

Chap. 8 Pulmonary and Antiallergy Agents Gleason, Perchonock, Torphy

79

-

PHOSPHODIESTERASE I N H I B I T O R S The pharmacodynami c s o f XANTHINES t h e o p h y l l i n e as an antiasthmatic were reviewed.95396 The o r i g i n a l view t h a t t h e bronchodi 1a t o r y a c t i o n o f theophyll i n e i s a t t r i b u t a b l e sol e l y t o an i n h i b i t i o n o f c y c l i c n u c l e o t i d e phosphodiesterase a c t i v i t y has become untenable and a1 t e r n a t i v e mechanisms were proposed.95~96 One o f these a1 t e r n a t i v e s , t h a t theophyll ine acts as an adenosine r e c e p t o r antagoni s t , was supported by a study indi c a t i ng t h a t theophyl 11ne p r e f e r e n t i a1 l y i n h i b i t s adenosine-induced bronchoconstriction i n asthmatic subjects.97 C1 e a r l y , much more evidence is needed before t h e "adenosine hypothesi s" can be accepted. One approach t o r e s o l v i n g t h i s issue i s t o develop s e l e c t i v e , h i g h a f f i n i t y adenosine receptor antagonists f o r c l i n i c a l evaluation. Steps toward t h i s process were taken by analyzing a s e r i e s o f 8-phen l x a n t h i n e s (31) f o r adenosine A]-receptor antagonist a c t i v i ty.68 These studies revealed t h e most p o t e n t A1-receptor antagonists t o be t h e 1,3-disubstituted n-propyl compounds, which have IC5os i n receptor b i n d i n g assays and p h y s i o l o g i c e f f e c t s a t concentrations 2-3 orders o f magnitude below those o f t h e o p h y l l ine.98 Sulfonamide s u b s t i t u t i o n a t t h e ~ a r aphenyl p o s i t i o n had l i t t l e e f f e c t on potency b u t g r e a t l y increased the aqueous s o l u b i l i t y o f these compounds.98 I n another study, t h e r e l a t i v e potency o f various 8-phenyl xanthi nes a t adenosine A1-receptors E. A2-receptors was determined .99 1,3-Di propyl-8-phenyl xanthi ne was somewhat s e l e c t i v e (23-fold) f o r A1-receptors over A2-receptors , whereas 8-(2-ami no4-chorophenyl)-l 3-dipropylxanthine was n e a r l y 400-fold more p o t e n t a t t h e Al-receptor. 49 The water-sol ubl e 8-Q-sul fophenyll-1.3dipropylxanthine d e r i v a t i v e s no longer possessed marked Al-receptor selectivity.99

The questions surrounding t h e p r e c i s e mechanism o f a c t i o n o f t h e o p h y l l i n e should g i v e new impetus t o the search f o r bona f i d e phosphodiesterase i n h i b i t o r s as p o t e n t i a l a n t i a l l e r g i c s and bronchodi l a t o r s . Moreover, t h e e x i stence o f several forms o f c y c l ic n u c l e o t i d e phosphodiesterases having d i f f e r e n t k i n e t i c c h a r a c t e r i s t i c s and t i s s u e d i s t r i b u t i o n s presents t h e i n t r i g u i n g p o s s i b i l i t y o f developing t f s s u e - s e l e c t i v e inflammatory c e l l s , airway smooth muscle) phosphodiesterase i n h i b i tors.100 Indeed, t h e biochemical responses t o one such compound, TVX 2706 (38). were evaluated i n several isol ated c e l l systems, 101 Thi s compound was found t o i n h i b i t s e l e c t i v e l y a low Km, CAMP-specific phosphodiesterase isozyme i n r a t polymorphonucl ear 1eukocytes , perha s account! ng f o r it s p o t e n t anti-inflammatory a c t i o n i n vivo.lop The synthesis and cardiac a c t i v i t y o f another s e r i e s o f s e l e c t i v e i n h i b i t o r s (39) o f t h e low Km, CAMP-spec1 f i c phosphodiesterase, were a1 so reported.m2

(e.s.,

An attempt t o combine t h e a c t i v i t y o f a 02-adrenoceptor a g o n i s t and a phosphodi esterase inhi b i t o r has been reported. 103

80

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ANTIHISTAMINES The pharmacology and therapeutic p r o f 1 l e s o f t h e non-sedatin histamine HI-receptor antagonists terfenadine104~105and astemizol el86 w e r e reviewed and p o t e n t i a l advantages o f these compounds over o l d e r agents were discussed.~07 The c l i n i c a l e f f i c a c y o f t e r f e n a d i n e and astemizole was compared i n studies o f p a t i e n t s w i t h hay fever-108-111 and chronic u r t i c a r i a . 1 1 2 The synthesis and pharmacology o f a s e r i e s o f N-heterocyclic 4-pi eridinamines @Q>, o f which astemizole (41)is a member, were descri bed. 183-1 15 A p r e l im i nary r e p o r t appeared on t h e s a f e t y and e f f i c a c y o f SK&F 93944 (421, a new non-sedating antihistamine, i n p a t i e n t s w i t h hay f e v e r . n 6 The synthesis and b i o l o g i c a c t i v i t y o f a novel class o f agents combining xanthine and HI-antihistamine moieties on the same molecule were d e s c r i b e d . l l 7

41

40 0

ti 42 -

ti

The r o l e o f histamine i n p r o ucing t h e signs and symptoms o f bronchial asthma was evaluated.1 8 H i s t o r i c a l l y , HI-antihistamines have been o n l y m a r g i n a l l y e f f e c t i v e i n preventing antigen-induced bronchoconstriction, perhaps because the sedative e f f e c t s o f c l a s s i c a l antihistamines l i m i t t h e i r therapeutic u t i l i t y , o r because histamine i s not a primary mediator o f a l l e r g i c asthma. The former proposal received support from recent studies where astemizole was shown t o b l u n t a n t i gen-i nduced bronchoconstri c t i o n i n a1 1e r g i c asthmatics. 118,119 Furthermore, both astemlzole120 and t e r f e n a d i ne121 were shown t o be e f f e c t i v e against exercise-induced asthma. Although t h e asthmatic response was not abolished i n any o f the studies c i t e d , t h e r e s u l t s suggest t h a t antihistamines ( p a r t i c u l a r l y t h e non-sedating agents) may have a r o l e i n the pharmacotherapy of bronchial asthma.

(m)

MEDIATOR RELEASE INHIBITORS - New t o p i c a l l y and o r a l l y a c t i v e M R I s continue t o be reported, a1though t h e p r e c i s e biochemical mechanism o f a c t i o n o f t h i s class o f a n t i - a l l e r g i c agents remains unknown. Nedocromil sodium (43) and minocromil (44) a r e t o p i c a l l y a c t i v e MRIs ( r a t PCA ID50 0.22 and 0.95 mg/kg intraderm., r e s p e c t i v e l y ) . Both compounds induce phosphorylation o f a 78,000 d a l t o n mast c e l l p r o t e i n , a process believed associated w i t h the biochemical mechanism by which they s t a b i l i z e these cells.122 AA-673 (451, an o r a l l y a c t i v e M R I , i s undergoing c l i n i c a l study.123 New o r a l l y a c t i v e M R I s i n c l u d e p y r i m i d i n y l ethenyloxani l a t e s ,124 t r i a z o l o q u i n o x a l inediones,l25 and i m i d a z o t r i a z i nes. l 2 6 NHMe

HO2C

0

C02H H02C

Pr 43 -

C02H Et

Pr

0

44 -

45 -

Chap. 8

Qulmonary and A n t i a l l e r g y Agents Cleason, Perchonock, Torphy

3

mRwcEs

2, 79 (1984). A. M. Leffer, Fed. Proc., g, 275 (1985). G. Feuerstein, J. Auton. Pharmacol., 2, 149 (1985). P. J. Piper, Int. Archs. Allergy Appl. Immunol., 76 (Suppl. l), 43 (1985). C.A. Higgs and S. Moncada, Drugs, 3, 1 (1985). R. A. Lewis, Chest, 86, 98s (1985). Y. Ishihara, Y. Uchida, S. Kitamura, Clin. Res., 3, 466 (1985). W. Schonfeld, M. Roller, J. Knoller, W. Konig, W. Muller, H. van der Hardt, J. Allergy Clin. Immunol., 75, 126 (1985). T. Isono, Y. Koshihara, S.-I. Murota, Y. Fukuda, S. Furukawa, Biochem. Biophys. Res. 486 (1985). Commun., J. T. Zakrzewski, N. C. Barnes, P. J. Piper, J. F. Costello, Br. J. Pharmacol., l9, 549 ( 1985 ). Y. Horiuohi, H. Saito, S. Nakajima, Annals Allergy, 55, 316 (1985). J.T. Zakrzewski, N. C. Barnes, P. J. Piper, J. F. Costello, Brit. J. Clin. Pharmacol., 19, 574 (1985). J. Smith, P. A. Creenberger, R. Patterson, R. D.Krel1, P. R. Bernstein, Am. Rev. Resp. Dis., lJl, 368 (1985). H. Bisgaard, S. Croth, F. Madsen, Br. Med. J., 290, 1468 (1985). G.E. Rovati, D. Oliva, L. Sautebin, G. C. Folco, A. F. Welton, S. Nicosia, Biochem. Pharmacol., 34, 2831 (1985). M. A. Lewis, S. Mong, R. L. Vessella, S. T. Crooke, Biochem. Pharmacol., 2,4311 ( 1985 1. S. Tucker, R. Muccitelli, T. Torphy, M. Wasserman, Pharmacologist, 7 , 129 (1985). R. J. Shaw, P. Fitzharris, 0. Cromwell, A.J. Wardlaw, A. 8. Kay, Allergy, 40, 1 (1985). J. T. Zakrzewski, N. C. Barnes, P. J. Piper, J. F. Costello, Prostaglandins, 28, 641 ( 1984). S. Mong, H.-L. Wu, M. 0. Scott, M. A. Lewis, M. A. Clark, B. M. Welchman, C. M. Kinzig, 316 (1985). J. C. Gleason, S. T. Crooke, J. Pharmacol. Exp. Ther., J. B. Cheng, D. Lang, A. Bewtra, R. G. Townley, J. Pharmacol. Exp. Ther., 232, 80 (1985). S. Mong, M.O. Scott, M. A. Lewis, H.-L. Wu, G. K. Hogaboom, M. A. Clark, S. T. Crooke, Eur. J. Pharmacol., 109, 183 (1985). Advances i n Prostaglandin, Thromboxane, and Leukotriene Research, Volume l4, J. E. Pike and D. R. Morton, Jr., Ed., Raven Press, New York (1985). J. Rokach and J. Adams, Acc. Chem. Res., l6, 87 (1985). E. J. Corey and W. Su, Tetrahedron Lett., 26, 281 (1985). J. Adams, 8. J. Fitzsimmons,Y. Girard, Y. Leblanc, J. F. Evans, J. Rokach, J. Am. Chem. SOC., 2,464 (1985). K. C. Nicolaou, C. A. Weale, S. E. Webber, H. Katerinopoulos, J. Am. Chem. Soc., 107, 7515 (1985). E. J. Corey, M. M. Mehrotra, W. Su, Tetrahedron Lett., 26, 1399 (1985). Y. Leblanc, B. Fitzsimmons, J. Adams, J. Rokach, Tetrahedron Lett., 26, 1399 (1985) B. J. Fitzsimmons and J. Rokach, Tetrahedron Lett., 26, 3939 (1985). K. C. Nioolaou and S. E. Webber. J. Chem. SOC.. Chem. Commun.. 297 (19851. 8. J. Fitzsimmons, J. Adams, . F:J Evans, Y. Leblanc, J. Rokach,-J. Biol. Chem., 260, 13008 (1985). H. G. Davies, S. M. Roberts, B. J. Wakefield, J. A. Winders, J. Chem. Soc., Chem. Commun., 1166 (1985). D. Pirillo, A. Cazzaniga, P. Leggeri, P. Ciaccone, G. Traverso, Farmaco, Ed. Sci., 40, 249 (1985). B. Spur, A. Crea, W. Peters, W. Konig, Arch. Pharm., 2,225 (1985). B. Spur, H. Jendralla, A. Crea, W. Peters, W. Konig, Arch. Pharm., 2,567 (1985). J. M. Fleisch, L. E. Rinkema, K. D. Haisch, D. Swanson-Bean, T. Coodson, P. P. K. Ho, W. S. Marshall, J. Pharm. Exp. Ther., 233, 148 (1985). P. I. Eacho, P. S. Foxworthy, W. D. Johnson, R. B. L. VanLier, Fundam. Appl. Toxicol., 5, 794 (1985). R. D. Dillard, F. P. Carr, D. McCullough, K. D. Haisch, L. E. Rinkema, J. H. Fleisch, Fed. Proc., 2, 491 (1985). Y. Guindon, International Conference on Leukotrienes and Prostanoids in Health and Disease, Tel-Aviv, Israel, Oct. 20, 1985. M. O'Donnell, D. Brown, N. Cohen, G. F. Weber, A. F. Welton, Annals Allergy, 278 (1985). c. D. Perchonock, I. Uzinskas, T. W. Ku, M. E. McCarthy, W. E. Bondinell, B. W. Volpe, J. G. Gleason, B. M. Weichman, R. M. Muccitelli, J. F. DeVan, S. S. Tucker, L. M. Vickery, M. A. Wasserman, Prostaglandins, 3, 75 (1985). T. W. Ku, M. E. McCarthy, B. Weichman, J. C. Gleason, J. Med. Chem., 28, 1847 (1985). C. D. Perchonock, M. E. McCarthy, K. F. Erhard, J. C. Gleason, M. A. Wasserman, R. M. Muccitelli, J. F. DeVan, S. S. Tucker, L. M. Vickery, T. Kerchner, B. M. Weichman, S. Mong, S. T. Crooke, J. F. Newton, J. Med. Chem., 3,1145 (1985).

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=,

a,

82

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- Pharmacodynamic Agents

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Chapter 9. Calcium Modulators

E. Wehinger and R. G r o s s , BAYER AG, Wuppertal-Elberfeld, FRG

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Introduction Calcium channel antagonists are important cardiovascular drugs which inhibit smooth and cardiac muscle contraction by blocking the influx of calcium ions through plasma membrane channels. Comprehensive surveys of their pharmacology and current and potential therapeutic use have The clinically well established drugs are verapami15, nifedipine' and diltiazem. In addition to nicardipine, three other calcium antagonists - gallopamil8 , nitrendipine', nimodipinel' have recently become commercially available.

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The discovery of 1,4-dihydropyridines (DHP) that increase the force of contraction by stimulating the influx of calcium ions in both smooth and cardiac muscle represents a major advance in the pharmacology of drugs that act directly on calcium channels." Recent electrophysiological and ligand binding studies have provided new insight into the mechanism of modulation of current flow through calcium channels. The ability of dihydropyridine compounds to either promote or inhibit calcium influx and the fact that both properties are observed dosedependently in the same dihydropyridine molecule, illustrate that these agents may really be looked at as calcium modulators. 12 Verapamil Analogues - In addition to verapamil Q), gallopamil (2) and tiapamil (2),some new compounds such as anipamil (5), desmethoxyverapamil (5 -), AQ-AH 208 and UL-FS 49 have been reported.

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ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21

Copyright 0 1986 by Academic Press, Inc. All rights of reproduction in any form reserved.

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- Pharmacodynamic Agents

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Gallopamil has been marketed for the prophylaxis and lon -term Piftherapy of coronary heart disease and atrial tachyarrhythmia. teen mg 2 to 3 times a day significantly improved symptoms of angina pectoris. l4 Detailed voltage clamp analyses of its mechanism of calcium channel blockade have shown that, in ventricular muscle, allo amil preferentially binds to open (activated) calcium channels.5 8 , l B The beneficial effect of tiapamil (RO 11-1781) in patients with coronary artery disease has been demonstrated after 200 to 800 mg of the drug. 16 Anipamil which is characterized by its long aliphatic side chain R3 is a new verapamil derivative with a long lasting antihypertensive action." From preliminary results on healthy volunteers about 100 mg p.0. anipamil, once dally, are expected to be clinically effective in an antihypertensive therapy. Deemethoxyverapamil (D 888) has only been used as a pharmacological tool. The (-)-isomer is 100 times more potent than its (+)-enantiomer at inhibiting Ca2+-induced tension in depolarized rat aortic strips as well as in decreasing force of contraction of cat papillary muscles. 19

'

Recently, several compounds have been developed as specific bradycardlc agents. One prototype is fallpamil (AQ-A 39, 6 ) which is chemically related to verapamil. Its antianginal efficacy has recently been demonstrated in a pilot study.2o Two congeners of falipmil are AQ-AH 208 (1)and UL-FS 49 (g). UL-FS 49 has been shown to decrease the

rate of spontaneously beating guinea pig atria at much lower concentratjons (EC30 = 0.03 pg/ml) than those at which it decreased the 108 pg/m1).21 In anesthetized dogs with contractility (EC30 ischemic myocardial perfusion, both compounds produced dose-dependent reductions In heart rate without major effects on aortic blood pressure or maximal left ventricular dP/dt and improved post-stenotic myocardial perfusion particularly to the subendocardium. 22

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Nifedipine Analogues Nitrendipine (lo) has been marketed as an antihypertensive drug with a longer duration of action than nifedipine (9).' Single oral doses, ranging from 5 to 40 mg, produced a prompt, safe and sustained hypotensive effect in patients with mild or moderate hypertension, the maximum effect being observed 1 to 3 hours

Calcium Modulators

Chap. 9

Wehinger, Gross

after dosing.23 In hypertensive patients with coronary artery disease who were inadequately controlled by a &blocker, a marked therapeutic response was obtained upon addition of nitrendipine. 24 Nimodipine (11). due to its predilective effect on spasms of cerebral vessels, has become the drug of choice in patients with subarachnoid hemorrhage. lo Its effectiveness in the prophylaxis of migraine has also been substantiated. 25 Moreover, nimodipine penetrates the blood-brain barrier and elicits some direct psychotropic activity.26 In rodents, it has been shown to attenuate aggressive behaviour and to interfere with postural reflexes. Anxiolytic properties have been demonstrated as has been a long lasting protective effect on hypoxia-induced retrograde amnesia. 26

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Section I1

- Pharmaoodynamic Agents

Bristol, Ed.

The superior potency of calcium antagonistic 1,4-dihydropyridines has initiated the development of a large number of related analogues, primarily as antianginal andfor antihypertensive agents. Nisoldipine (BAY K 5552, 11) is one of the most potent blockers of voltage-dependent Ca2+-channels (IC50=l. lxlO-’ M) and is characterized by its predominant vasodilating effects on coronary and peripheral blood vessels. 27-28 KC1-induced contractions of aortic strips treated with nisoldipine (2.9~10’~ M) remained inhibited €or 15 hours. 27 Nilvadipine (FR-34235, 13) demonstrates a similar effect as nifedipine on KC1-induced responses in venous smooth muscle. However, it is much more potent than nifedipine against contractions which are mediated by activation of postsynaptic o(l-adrenoceptors.29 Darodipine (PY 108-068, 2)appears to change the rank order of the negative chronotropic and negative inotropic effects of calcium antag o n i s t ~ .Isrodipine ~~ (PN 200-110, g) has a longer duration of action than darodipine and has been shown to cross the blood brain barrier without stimulating any CNS effects.31 The earlier report on felodipine (H 154-82, 2)suggesting interaction with ~ a l m o d u l i nas ~ ~ the basis of its vasodilating activity has been challenged, mainly due to the different concentration range of its calcium antagonism and calmodulin binding.33s34 In vitro studies of flordipine (RH 2906, have provided some evidence that it is metabolized to (not yet identified) com ounds which may contribute to its in vivo antihypertensive activity.” MDL-72567 (18), a “beto-dihydropyridine”, has been suggested to induce, in contrast to nifedipine, in vivo a depressant effect on the sinus node. 36

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Amlodipine (UK-48340, 2)is a new antihypertensive and antianginal DHP derivative on a once-daily dose basis. In hypertensive dogs 0.5 to 2 mglkg amlodipine reduce the blood pressure gradually, with maximum reduction occurring between 3.5 to 7 hours after application.37 Bioavailability in dogs has been demonstrated to approach 100%.38

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Bepridil (20) has recently been confirmed to Other Structures inhibit the potential-operated calcium channel and related isometric tension development in vascular smooth rn~cle.~’*40 In isolated cardiac preparations as well as in in vivo studies the drug has been shown to be a selective coronary v a ~ o d i l a t o r .*42 ~ ~ At concentrations which antagonize calcium dependent mechanisms in vascular smooth muscle it appears to inhibit the activity of c a l m o d ~ l i n .Clinical ~~ experience has proven that a daily dose of 300 to 400 mg bepridil is effective in the management of stable angina. 44 There is some evidence that in addition to blocking slow channels bepridil also influences fast sodium currents.45 This dual action in myocardial cells implies that it is a class I as well as a class IV antiarrhythmic agent according to the Vaughan-Williams claseificat i ~ n . In ~ ~anesthetized dogs bepridil increases the refractorinees of atrial myocardium, atrial ventricular nodal tissue and ventricular myocardium. 47-49 It prevents andfor terminates experimental supraven-

Calcium Modulators

Chap. 9

Wehinger, Gross

9

tricular4 and ventricular50*51 arrhythmias in a variety of animal models and increases the ventricular fibrillation threshold during both unobstructed coronary blood flow and regional myocardial ischemia 50

.

appears to be a novel calcium antagonist with a seHA-1004 (2) lective vasodilatory action. In depolarized rabbit aorta it produced a competitive inhibition of calcium induced c~ntraction.~' Isolated guinea pig left atria or right ventricular papillary muscles did not respond to the drug. Due to its antagonizing effect on phenylephrine induced contractions of rabbit aorta in the absence of extracellular calcium, it has been suggested that HA-1004 affects intracellular rather than extracellular calcium. The in vitro inhibition of agonist induced contractions of canine renal arteries has been confirmed by an increase of renal blood flow in anesthetized dogs. 53

x

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C H,OC H2CH (C H3I2 21

20 -

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Mechanistic Aspects It is well established that calcium channel antagonists serve as potent and selective inhibitors of plasmalemmal Ca2'-entry through voltage-depedent calcium channels. 54 Evidence for a specific mode of action is based on structure activity relationships, including stereoselectivity, that have been described for the major classes of these agents.55 The existence of discrete binding sites for calcium antagonists and agonists has been established by intensive studies of radio-labeled, mainly 1,4-dihydropyridine-type, li and binding to membrane preparations as well as to intact cells. 5%-59 Thus, specific, high affinity, reversible and stereoselective binding is found in a variety of tissues including vascular and non-vascular smooth muscle, cardiac muscle, skeletal muscle and brain. It has been demonstrated on the basis of X-ray crystallographic. analyses of 1,4-dihydropyridines with restricted conformational flexibility that the DHP molecule interacts with the binding site preferably in a conformation in which the plane of the phenyl ring bisects the DHP ring.60

Correlations between tissue binding and pharmacological activities have been sought in a number of systems for which -1,4-dihydropyridine binding has been demonstrated. The best correlations are those for smooth muscle where essentially 1:l correlations can be obtained between inhibition of binding and inhibition of K+-depolari-

['q

90

Section I1

- Pharmaoodynamic

Agents

Bristol, Ed.

zation-induced mechanical response. 61-63 In myocardium, however, the -nitrendipine binding is 2 equilibrium dissociation constant % of to 3 orders of magnitude lower than the concentration of nitrendipine which produces half maximal pharmacological effects. 64 Electrophysiological data suggest that calcium channel blockade by nisoldipine, nitrendipine and nicardipine in heart muscle is strongly modulated by membrane potential, with blockade being more pronounced at less negative holding This voltage dependence has been interpreted in terms of the modulated receptor hypothesis and suggests that the high affinity site probably represents binding to and stabilizing of the inactivated state of the channel in which no openings occur, Recent studies of changes in binding to intact polarized and depolarized ventricular myocytes have demonstrated that with depolarization the number of pH] -nitrendipine binding sites (Bmax) is significantly in~reased.'~ However, there was no difference in KD between polarized and depolarized cells.

pq

Competition of PH] -1,4-dihydropyridine binding with DHPs is consistent with competitive antagonism. This fs also true for the competitive interactions between 1,4-dihydropyridine agonists and antagonists indicating that they bind to the same calcium channel receptor site.58s59968 The inhibition of f3H] -1,4-dihydropyridine binding by other calcium antagonists has disclosed apparent different sites of action of these drugs. It is now generally agreed that verapamil, gallopamil and desmethoxyverapamil act at a site distinct from the 1,4-dihydropyridine binding site and that they should be classified as negative heterotropic allosteric effectors due to their inhibition of P H ] -1,4-dihydropyridine binding. 63 In marked contrast, diltiazem actually stimulates 1,4-dihydropyridine binding over its pharmacologically effective dose range either by increasing ,,B (smooth muscle, skeletal muscle) or decreasing KD (cardiac tissue, brain) .613 6 9 This positive heterotropic allosteric interaction between diltiazem and the 1,4-dihydropyridines could also be demonstrated in tissue experiments, both in cardiac and smooth muscle.70s71

PH] -1,4-dihydropyridines have been used to determine the molecular properties of the binding site in the Ca2+-channe1.72-74 In skeletal muscle, radiation-inactivation experiments have shown that the size of the dihydropyridine binding domain is decreased in the presence of d i l t i a ~ e m .It ~ ~ has been suggested that the channel may be composed of subunits and that channel drugs not only alter channel function but simultaneously change the architecture of the ionic pore. The model of three drug receptor sites which are linked to each other (and to calcium binding sites) via heterotropic allosteric coupling mechanisms has recently been described, 76 Calcium Agonists - Only minor changes of the 1,4-dihydropyridine structure led to compounds which exhibit pharmacological actions opposite to those of nifedi ine: instead of inhibiting they increase the force of contraction. 77948 BAY K 8644 (11)is the most thoroughly

Chap. 9

Calcium Modulators

Wehinger, Gross

91

studied prototype of these agents. It exerts both in vitro and in vivo positive inotropic, vasoconstrictive and moderate positive chronotropic activity in a concentration range from''01 to M.11*79J80 Using 45Ca2+, increased Ca-inf lux during cellular depolarization could be correlated with enhanced electromechanical coupling. 81 y82 Electrophysiological studies have shown that the prolongation of the plateau phase of the cardiac action potential is indicative of increased Ca2+-inf lux and the consequent increase in contractility,83 Investigations of the single Ca2+-channel kinetics with BAY K 8644 have revealed that this compound dose-dependently keeps the channel in the open state for a longer In addition to BAY K 8644 other dihydropyridines with calciumagonistic properties have been disclosed. CGP-28392 (%) also exerts The active dosepositive inotropic and vasoconstricting range is about one order of magnitude higher than that of BAY K 8644. In vivo its positive inotropic. response appears to be less pronounced than its vasoconsttictive properties .88 The main pharmacological effect of YC-170 (3)is vascular contraction. It is about 3 times less potent than CGP-28392 and dis la s minimal positive inotropic and no positive chronotropic activity. H 160/51 (2)has also been shown to be a calcium agonistic dihydropyridine with an EDs0 of 1 UM in cat papilCompound 202-791 lary muscles and in a portal vein preparation. 'lSg2 (25) exerts positive inotropic and vasoconstricting effects by increasing Ca2+-influx.93 As with BAY K 8644 it has been shown that the Ca2+-modulating effect of 202-791 is strongly dependent on membrane potential. It is an agonist under well-polarized conditions. However,

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Section I1

- Pharmacodynamic Agents

Bristol, Ed.

when the cell is depolarized, it is converted to an a n t a g o n i ~ t . ~ ~ , ~ ~ This result, together with the finding that high drug concentrations also reverse the calcium agonism to calcium antagonism, brought up hypotheses on the molecular basis of the calcium modulating properties of 1,4-dihydropyriclines. * 95 The recent observation that only the (-)-enantiomer of BAY K 8644 and the (+)-enantiomer of 202-791 are responsible for the calcium agonistic effect while the optical antipodes are calcium antagonists, strongly underscore the close structural vicinity of calcium antagonism and calcium agonism in this class of drugs. 93,96

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Several calcium antagonists are under development. In Conclusions addition to pure vascular affects parenchymal activity, e.g. in the brain, could be demonstrated. Knowledge of the basic mechanism of modulation of calcium currents has considerably increased due to electrophysiological and ligand binding studies as well as to the discovery of calcium agonists. The latter are pharmacological tools and provide a novel mechanism of positive inotropir. activity which may lead to new drugs €or the treatment of congestive heart failure.

1.

2.

3. 4.

5. 6.

7. 8.

9. 10.

11. 12.

1314. 15.

16. 17. 18. 19. 20. 21. 22 * 23. 24.

H. Meyer, S. Kazda, and P. Bellemann, Annual Reports in Medicinal Chemistry, 2, 79 (1983). P.H. Stone and E.M. Antman, Eds., Calcium Channel Blocking Agents in the Treatment of Cardiovascular Disorders, Futura Publishing Company, Mount Kisco, New York, 1983. L.H. Opie, Ed., Calcium Antagonists and Cardiovascular Disease, in: Perspectives in Cardiovascular Research, Vol. 9, Raven Press, New York, 1984. A. Fleckenstein, C. van Breemen, R. Gro8, and F. Hoffmeister, Eds., Cardiovascular Effects of Dihydropyridine-Type Calcium Antagonists and Agonists, Springer-Verlag, Berlin, Heidelberg, New York, Tokyo, 1985. S. Baky, in: New Drugs Annual: Cardiovascular Drugs, Vol. 2, A. Scriiabine, Ed., Raven Press, New York, 1984, p. 71. E.M. Sorkin, S.P. Clissold, and R.N. Brogden, Drugs 3, 182 (1985). M. Chaffman and R.N. Brogden, Drugs 3, 387 (1985). M. Kaltenbach and R. Hopf, Eds., Gallopamil, Pharmakologlsches und klinsches Wlrkprof11 eines Kalziumantagonisten, Springer-Verlag, Berlin, Heidelberg, New York, Tokyo, 1983. A. Scriabine, S. Vanov, and K. Deck, Eds., Nitrendipine, Urban and Schwarzenberg, Baltimore-Munich, 1984. E. Betz, K. Deck, and F. Hoffmeister, Eds., Nimodipine, Pharmacological and Clinical Properties, F.K. Schattauer Verlag, Stutgart, New York, 1985. M. Schramm, G. Thomas, R. Towart, and 0. Franckowiak, Nature 535 (1983). C. Thomas, R. Gro8, and M. Schramm, J. Cardlovasc. Pharmacol. 5, 1170 (1984). Drugs of the Future 2, 108 (1984). M. Sucic and J. Schicmann. Arzneim.-Forsch./Drug Res. 3. 1587 (1984). T.F. McDonald, D. Pelzer, and W. Trautwein. J. Physiol. 352, 217 (1984). M. Maltz, M. Wiseman, J. O'Keefe, and A.J. C a m , Eur. Heart J. 6 , Suppl. 1. 1 1 1 (1985). J. Gries and K. Feilner, Therapiewoche 2,6390 (1984). H. Mliller-Peltzer, E. Brode, G. Greger, H.D. Lehmann, and M. Hollmann, International Symposium on Cardiovascular Pharmacotherapy. Geneva, April 22-25. 1985, Abstr. 204. H. Nawrath and M. Raschak, J. Mol. Cell. Cardiol. 16, Suppl. 3, 14 (1984). S. Jost, W. Schulz, and G. Kober, Arzneim.-Forsch,/Drug Res. 35, 1279 (1985). W. Kobinger and C. Lillie, Eur. J. Pharmacol. 104. 9 (1984). J.W. DZmmgen, K.A. Lamping, and G.J. Cross. J. Cardiovasc. Pharmacol. 7, 71 (1985). K. Deck, K. Stoepel. D. Leibowitz, R. Taylor, Jr. and S . Vanov. in: NiFrendipine, A. Scriabine. S. Vanov. and K. Deck, Eds.. Urban & Schwarzenberg, Baltimore-Munich, 1984, p. 397. A.T. Tammen. K. Stoepel. H. Vollmer. and G. Blitmchcn, in: Nitrendipine, A. Scriabine. S. Vanov, and K. Deck, Eds., Urban h Schwarzenberg. Baltimore-Munich, 1984. p. 469.

m,

Chap. 25.

26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58.

59. 60. 61. 62. 63. 64. 65. 66. 61. 68. 69. 70. 71.

9

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Wehinger, Gross

2

H.J. Gelmers. in: Nimodipine, Pharmacological and Clinical Properties, E. Betz, K. Deck, and F. Hoffmeister, Eds., F. K. Schattauer Verlag. Stuttgart, New York 1985, p. 421. F. Hoffmeister, H.P. Bellemann, U. Benz, and W. van den Kerckhoff, in: Nimodipine, Pharmacological and Clinical Properties, E. Betz. K. Deck. and F. Hoffmeister. Eds.. F. K. Schattauer Verlag, Stuttgart, New York 1985, p. 77. S. Kazda, B. Garthoff, K.D. Rhsch, and G. Schliiter, New Drugs Annual: Cardiovascular Drugs. Vol. 1, A. Scriabine, Ed., Raven Press. New York. 1983. p. 243. , H. Suzuki, Br. J . Pharmac. 3.243 (1984). T. Itoh, Y. Kanmura, H. K ~ ~ i y a m aand K.F. Jim and W.D. Matthews. J. Cardiovasc. Pharmacol. 1, 458 (1985). Y. Wada. K. Satoh. and N. Taira, J . Cardiovasc. Pharmacol. 5. 881 (1984). K. Kordenat. J. Leasure, 9th. Intern. Congress Pharmacol. London, July, 30-August 3. 1984. Abstr. 895P. S.L. Bostrh, B. Ljung, S. Mardh, S. Forsen, and E. Thulin. Nature 292. 777 (1981). J.D. Johnson and D.A. Fugman, J. Pharmacol. Exp. Ther. 226. 330 (1983). A.R. Lorimer, D. Elmfeldt, G. Johnsson, and A. Ward. Drugs 2,Suppl. 2. 1 (1985). P.S. Wolf, D.V. Romano, D. Lester, L. Choi, T.P. PKUSS, and R.D. Smith, Fed. Proc. 43, 552, Abstr. 1563 (1984). Spedding, M. Gittos, G.F. DiFrancesco, M. Petty, 2nd. Europ. Meeting on Hypertension. June 9-12, 1985, Milan, Abstr. 495. M.G. Dodd and I. Machin, Proc. Br. Pharmacol. SOC., April 10-12, 1985, Cardiff, Abstr. P55. A.P. Beresford, M.J. Humphrey, and D.A. Stopher, PKOC. BK. Pharmacol. SOC., April 10-12. 1985. Cardiff, Abstr. P53. E. Apoil and E. Schhbaum, Prog. Pharmacol, 5/4, 153 (1985). S.F. Flaim, P.H. Ratz, S.C. Swigart, and M.M. Gleason. J . Pharmacol. Exp. Ther. 234, 63 (1985). r A n n o , T. Furuta, M. Itoh, I. Kodama, J . Toyama. and K. Yamada, Br. J . Pharmacol. 81. 41 (1984). P.D. Verdouw and M.G. Scheffer, Arzneim. Forsch./Drug Res. 2.21 (1984). C. Lugnier, A. Follenius, D. Gerard, and J.C. Stoclet, EUK. J . Pharmacol. 98, 157 (1984). K.A. Narahara, W. Shapiro, I. Weliky, and J. Park, Am. J. Cardiol. 2,29 (1984). E. Winslow and K.A. Kane, J . Cardiovasc. Pharmacol. 2, 655 (1981). E.M. Vaughan-Williams, J . Clin. Pharmacol. 2,129 (1984). A. Sassine, C. Masse, A. Fajuri, J.L. Hirsch, C. Labrid. and P. Puech, Am. J . Cardiol. 2,1707 (1984). N. Raghaven, M. Scharf, G. Keren, 8. Butler, D. Weiner, D.S. Miura, and J.C. Somberg, Clin. Res. 2,632 A (1983). M.D. Brannan, M.A. Fortunato, and S . F . Flaim, Fed. Proc. 43. 960 (1984). J.J. Lynch, R.G. Rahwan, and B.R. Lucchesi, Eur. J . Pharmacol. 111,9 (1985). C.V. Jackson. S.E. Mitsos, P . J . Slmpson, E.M. Driscoll, and B.R. Lucchesi, Pharmacology 30. 320 (1985). T. Asano and H. Hidaka, J. Pharmacol. Exp. Ther. 231. 141 (1984). 454 (1985). T. Asano and H. Hidaka, J. Pharmacol. Exp. Ther. B.P. Bean, J . Gen. Physiol. 86, 1 (1985). R.A. Jania and D.J. Triggle, J . Med. Chem. 26, 775 (1983). R.J. Miller and S.B. Freedman, Life Sciences 2,1205 (1984). R.A. Janis and D.J. Triggle, Drug Dev.Res. 6, 257 (1984). P. Bellemann, FEBS Letters 167, 88 (1984). R.A. Janis. D. Rampe, J.G. Sarmiento, and D.J. Ttiggle. Biochem. Blophys. Res. Comm. 121. 317 (1984). W. Seidel, A. Meyer. L. Born, S. Kazda, and W. Dompert. In: QSAR and Strategies in the Design of Bioactive Compounds, J.K. Seydel, Ed., VCH Verlagsgesellschaft. Weinheim. 1985. p. 366. G.T. Bolger, P. Gengo, R. Klockowski, E. Luchowslti. H. Siegel. R.A. Janis. A.M. Triggle, and D.J. Triggle, J. Pharmacol. Exp. Ther. 225. 291 (1983) P. Bellemann. A. Schade, and R. Towart, Proc. Natl. Acad. Sci. USA 2356 (1983). D.J. Trfggle and R.A. Janis in: Modern Methods in Pharmacology, Vol. 11, N. Back and S. Spector, Eds., A.R. Liss, Inc. New York, N.Y., 1984, p . 1 . K.S. Lee and R.W. Tsien, Nature 302, 790 (1983). M.C. Sanguinetti and R.S. Kass, Circ. Res. 2,336 (1984). B.P. Bean, Proc. Natl. Acad. Sci. USA g ,6388 (1984). F.J. Green. B.B. Farmer, G.L. Wiseman, M.J.L. Jose, and A.M. Watanabe, Circ. Res. 56, 576 (1985). K A . Langs and D . J . Triggle, Mol. Pharmacol. 27, 544 (1985). H. Glossmann, D. Ferry, and C.B. Boschek, Naunyn Schmiedeberg's Arch. Pharmacol. 323, 1 (1983). T D e Pover, I.L. Grupp, G. Grupp, and A. Schwartz, Biochem. Biophys. Res. Comm. 114, 922 (1983). F. Yousif and D.J. Triggle, Can, J. Physiol. Pharmacol. 63, 193 (1985).

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94 72.

73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87 * 88. 89. 90. 91. 92. 93. 94. 95. 96.

Section I1

- Pharmacodynamic Agents

B r i s t o l , Ed.

J.C. Venter, C.M. Fraser, J . S . Schaber, C.Y. Jung, G. Bolger, and D.J. Triggle. J. Biol. Cham. 258, 9344 (1983). M. Borsotto, J. Barhanin. R.I. Norman, and M. Lazdunski, Biochem. Biophys. Res. Comm. 122, 1357 (1984). A. Rengasamy, J. Ptasienski. and M.M. Honey, Biochem. Biophyn. Rcs. Conm. 126. 1 (1985). A. Goll, D.R. Ferry, and H. Glosemann. PEBS Letters 157. 63 (1983). H. Glossmann, D.R. Ferry. A. Goll, J. Striessnig. and G. Zernig. Arzneim.-F0rsch.l Drug Res. 2,1917 (1985). M. Schramm and R. Towart, Life Sciences 97, 1843. (1985). K.C. Preuss. G . J . Gross, H.L. Brooks, and D.C. Warltier, L i f e Sciences 21, 1271 (1985). R. GroE, M. Kayser, M. Schram, R. Taniel, and G. Thomas, Arch. Int. Pharmacodyn. Ther. 277, 203 (1985). P.L. Vaghy, J.L. Grupp, and A. Schwartz, Circ. Res. Is, 549 (1984). M. Schramm, R. Towart. B. Lamp, and G. Thomas, J. Cardiovasc. Pharmacol. 1, 493 (1985). K.S. Hwang and C. van Breemen. Europ. J. Pharmacol. 116. 299 (1985). G. Thomas, M. Chung. and C.J. Cohen, Circ. Res. 87 (1985). P. Hese, J.B. Lansman, and R.W. Tsien, Nature 311, 538 (1984). S. Kokobun and H. Reuter, Proc. Natl. Acad. S c i . U S A S , 4824 (1984). R. Ochi, N. Hino, and Y. N i i m i , Proc. Jap. Acad. 60. 153 (1984). P. Erne, E. Burgisser. F.R. BUhler, B. Dubach, H. Kuhnis, M. Meier, and N. Rogg, Biochem. Blophys. Res. Comm. 118. 842 (1984). K.C. Preuss, N.L. Chung, H.L. Brooks, and D.C. Warltier, J. Cardlovasc. Pharmacol. 6 , 949 (1984). H. Rogg, L. Criscione, A. Truog, and M. Meier, J. Cardiovasc. P h a m c o l . 1 Suppl. 6, S31 (1985). T. Takenaka and H. Maeno, Jap. J. Pharmacol. 2. 139P (1982). Gj(lr6trup and Harding. J. Mol. Cell. Cardiol. 17. Abstr. 171 (1985). T. Byer, P. Gj6rstrup. and U. Ravens, Naunyn Schmiedeberg's Arch. Pharmacol. 330, 142 (1985). R.P. Hof, M.T. Riiegg. A. Hof. and A. Vogel. J. Cardiovasc. Pharmacol. 1. 689 (1985). M.C. Sanguinetti and R.S. Kass, J. Hol. Cell. Cardiol. 16. 667 (1984). P.L. Vaghy, J.L. Grupp, G. Grupp, J . L . Balwierczak, J . S . Williams, and A. Schwartz, Europ. J. Pharmacol. 102, 373 (1984). G. Pranckowiak, M. Bechem, M. Schramm, and G. Thomas, Europ. J. Pharmacol. 114, 223 (1985).

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Chapter 10.

Class I And TI1 Antiarrhythmic Drugs

Mitchell I. Steinberg, William B. Lacefield, and David W. Robertson Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN 46285

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Introduction Nearly 10 years have elapsed since the local anesthetic antiarrhythmic drugs (class I ) were reviewed in this series.l Drugs that prolong action potential duration (APD) selectively (class 111) were last discussed in 1983.2 An abundance of reviews on the electrophysiological basis of cardiac arrhythmia^^-^ and therapeutic use of antiarrhythmic drugs6-8 have appeared recently. The large volume of new information has mandated that we limit our discussion to class I and I11 agents, with emphasis on new compounds that appeared in the literature during the last three years. However, recent reports relevant to the mechanism of action of older agents will also be mentioned. The Vaughan Williams classification recognizes four distinct antiarrhythmic g r o ~ p s . ~Class I agents may be further divided into three subgroups on the basis of effects on APD.1° The potent conduction depressants flecainide, encainide and lorcainide are Ic agents that have little effect on APD, while lidocaine, tocainide and mexiletine are examples o f Ib compounds that shorten APD. Quinidine, disopyramide and procainamide represent Ia agents that prolong repolarization.l 1 In addition, the observation that local anesthetics possess unique affinities for the sodium channel depending on whether the channel is in the resting, open or inactivated state (modulated-receptor hypothesis), l2 has provided added biophysical support for the subclassification of class I drugs. Thus, Ib agents tend to rapidly associate with and dissociate from open and/or inactivated sodium channels with time constants in the 100-300 msec range, while Ic agents require tens of seconds for block onset and recovery; Ia agents are intermediate.11'13 The emergence of programmed electrical stimulation (PES) techniques for the clinical evaluation of antiarrhythmic drugs continues to have an important impact on the way new drugs are tested.14 A positive response to a drug in a standardized PES protocol portends a high probability of success upon long-term treatment, although a negative drug response does not necessarily predict failure.15'16 In patients with sporadic, lifethreatening arrhythmias, PES rather than Holter recording may be the preferred method of drug evaluation.l 7 Improved animal models are available to simulate PES-induced arrhythmias in humans.18' l9 The induced tachycardias seem to be reentrant in origin and respond Nevertheless, some evidence predictably to antiarrhythmic drugs.* O suggests that, in terms of rate, morphology and reproducibility, these models may not adequately mimic the typical monomorphic reentrant ventricular tachycardia that appears to be the best clinical predictor of drug efficacy.21'22 An animal model that causes "sudden cardiac death" may also be relevant to new drug e v a l ~ a t i o n . This ~~ model involves electrically induced thrombus generation within the circumflex coronary artery in dogs having had a prior infarct in the distribution of the left anterior descending coronary artery. ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21

Copyright 0 1986 by Academic Press, Inc. All rights of reproduction in any form reserved.

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Class I: Update on established agents - Recent reviews on the pharmacology and mechanism of action of standard agents such as q ~ i n i d i n e , ~ ~ procainamidc,24’25 d i ~ o p y r a m i d e ~ ~and lidocaine26 have appeared. Symposia and reviews of the electrophysiology and therapeutic use of newer type I agents including p r ~ p a f e n o n e , pirmenol,28 ~~ tocainide,2 9 mexilitine,30 lorcainide,3 1 e n ~ a i n i d e ~and ~ f l e ~ a i n i d e ~have ~ also been published. Class I agents interact weakly with resting sodium channels at normal resting membrane potentials; activation is required before these agents block (use-dependency) . 12’l3 Lidocaine interacts with both open and inactivated channels, whereas quinidine and amiodarone preferentially interact with open and inactive channels, respectively. l2 Separate mechanisms mediating resting and use-dependent block were distinguished using propafenone and structural analogs.34 Regardless of which channel state is preferentially blocked by class I drugs, the unblocking rate directly determines the amount of depression present at normal heart rates. Since the Ic agents like flecainide,13’35 encainide,l3 and lorcainide3’ possess long recovery time constants, these compounds tend to depress conduction velocity in normal and especially depolarized myocardium at all physiologically relevant heart rates. The Ib agents with short time constants show little accumulation of block between impulses; early or rapid impulses are preferentially blocked. 11’12 In general, small molecular size, high lipid solubility, and low pKa favor a fast unblocking rate for class I drugs.13’36’37 Competition studies have added strong support to the notion that class I drugs act on a common receptor site, but possess selective affinities for different sodium channel states. For example, high concentrations of lidocaine relieved sodium channel block caused by bupivicaine, an agent that acts on inactivated channels and dissociates much more slowly than lidocaine.38 Competition interactions between propafenone and lidocaine acting on different sodium channel states have also been described.39 The use-dependent effects of lidocaine in dog Purkinje fibers were specifically inhibited by SC 7 2 1 4 , a monoclonal antibody against the electroplax fast sodium channel. However, in this case, SC 7214 and lidocaine did not appear to interact at a common site within the channel.4 0 Metabolites of several antiarrliythmic drugs are pharmacologically important and continue to be extensively investigated. Encainide’s two major metabolites, 3-methoxy-O-demethyl encainide and O-demethyl encainide (ODE) possess antiarrhythmi~~l and class I electrophysiological proper tie^.^^ ODE, especially in ischemic tissues, may be likely to cause profound conduction depression43 and, like flecainide,44 may induce arrhythmias in dogs with infarcted hearts. 41 In anesthetized dogs, the electrophysiological effects of lorcainide and its N-dealkylated metabolite, norlorcainide, are qualitatively and quantitatively similar.45 However, the O-dealkylated metabolites of flecainide are only 1 / 2 t o 1/10 as active as f l e ~ a i n i d e . ~Acecainide ~ (NAPA), the rapidly formed N-acetyl metabolite of the class I agent, procainamide, is a selective class I11 Since NAPA, unlike procainamide, does not induce a lupus-like syndrome, it has been investigated clinically, but the results have been e q u i v o ~ a l . ~ ~The ’ ~ ~pharmacokinetics and electrophysiology of the desisopropyl metabolite of disopyramide have been investigated. The authors concluded that this metabolite contributes significantly to the anticholinergic side-effects seen during disopyramide therapy.

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Effects of stereochemistry on activity of chiral antiarrhythmics remains an underdeveloped area. The L-isomer of disopyramide was found to be more potent than its enantiomer in slowing sinus rate and increasing AV-nodal refractoriness.51 The two enantiomers of flecainide were found to be equipotent in suppressing chloroform-induced ventricular fibrillation (VF) in mice and ouabain-induced ventricular tachycardia (VT) in dogs. 5 2 Conformational perturbations produced by an intramolecular hydrogen bond between the amide and pyridine moieties of disopyramide appear to increase the ratio of antiarrhythmic to anticholinergic activity; model compounds were prepared to test this hypothesis.53 Antiarrhythmic effects of quaternary ammonium class I agents were further characterized @. The quaternary analogs of propranolol, UM-27ZS4 or UM-424,” were studied after oral administration to dogs with chronic infarcts. UM-272 reduced the incidence of VF in the acute thrombosis model but not the accompanying VT. UM-272 possessed typical Ia electrophysiological effects including marked use-dependent sodium channel block with a block recovery half-time of 7 sec.56 UM-424 abolished VT induced by PES by decreasing conduction preferentially in the ischemic zone and increasing refractoriness in normal zones.5 5 Class I: Recently reported new chemical entities - Several new class I agents possessing the $-antagonist pharmacophore have been reported. Diprafenone (1) is a recently reported propafenone congener. It is more potent than propafenone, and displays maximum antiarrhythmic activity at doses which have only minor depressant effects on intraventricular conduction and hemodynamics. 5 7 Compound 711389-S (2) was active against aconitine and ouabain-induced arrhythmias.5 8 ’ 5 9 Detailed electrophysiological evaluation in guinea pig muscle indicated 2 is a class Ia antiarrhythmic with less anticholinergic activity than either disopyramide or quinidine. 6 o Several lines of evidence indicate $-receptors are not involved in its antiarrhythmic effect. In guinea pig atria 2 was considerably less potent than propranolol as a $-antagonist (pA;s = 5 . 2 9 and 8.62, respectively), but was more potent as an antiarrhythmic; moreover, there were no significant differences in

antiarrhythmic activities of the R and S enantiomers.5 8 Nicainoprol (RU-42924, 3 ) is a class Ib drug with moderate p-blocking activity; unlike propafenone, 3 has no significant negative inotropic potential.61’62

A number of compounds bearing the 2,6-dimethylanilide substructure

of lidocaine have been reported. SUN-1165 (4) contains the highly basic pyrrolizidinyl moiety instead of the less basic diethylamine group of

’’

lidocaine. Electrophysiological studies & vitro revealed that 4 is a Class Ib d r ~ g . ~Compared ~ ’ ~ ~to lidocaine and disopyramide, the compound had less CNS toxicity and anticholinergic activity, respectively.66 Another Ib lidocaine-like agent is recainam (WY-423262) ( 5 ) . Therapeutic i.v. doses failed to produce CNS or negative inotropic side-effects in

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and the drug safely and effectively reduced PVC’s in man.68 Droxicainide (ALS-1249, 6) was reported to have anti-arrhythmic and local anesthetic properties that are qualitatively similar to lido~ a i n e , ~ ~ but ’ ’ ~with a better therapeutic index in 24 hr infarct dogs than lidocaine. The piperidine and azepine analogs of droxicanide which lack the hydroxyethyl moiety are also active. 72

Stout and co-workers have conducted extensive studies on the SAR of changrolin (1) to eliminate untoward side-effects (skin discoloration and anticholinergic activity) of the parent compound. The bis(pyrro1idinylmetbyl)phenol portion of 1 was optimal for antiarrhythmic activity, but the quinazoline moiety could be varied considerably while maintaining activity.73 Replacement of the quinazoline ring with a variety of substituted benzoyl groups resulted in several potent antiarrhythmics with minimal anticholinergic activity.7 4 Further SAR studies led to the selection of ACC-9358 (8) for development. 7 5 Electrophysiologically, these compounds appear to be Class I agents. ”

-7

8

-9

Disopyramide continues to serve as a prototype for new antiarrhythmics, A series of compounds in which the phenyl group of disopyramide was replaced with alkyl moieties was synthesi~ed.’~ One of the compounds in this series, propisomide (CM-7857, F), was reported to possess a longer duration of action, fewer neurologic and gastrointestinal side-effects and less anticholinergic activity than disopyramide. 7 9 As with disopyramide, the major metahol ite in both plasma and urine was the‘mono-N-dealkylated analog.80 A single oral dose of 9 was compared to a variety of other antiarrhythmics in 10 patients. The compound was effective in 6; it increased PQ intervals, and had no The pyridyl portion of disopyramide effects on QRS or QTc intervals.’l can be modified considerably, and some reduced bicyclic analogs were prepared.82 The optimal compound of the series, SC-36602 (lo), is currently in clinical trials. A series of animal studies revealed that 10 is a Class I agent; moreover, it did not produce adverse CNS or negative inotropic effects, and possessed only about 7% of the anticholinergic activity of disopyramide.83-85

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(u)

AHR-10718 is the optimal compound in a series of aminoethylureas that suppressed arrhythmias in the ouabain-intoxicated and Harris dog models. The drug caused a use-dependent decrease in action potential upstroke velocity (V ) , Purkinje fiber conduction velocity and APD.86 Carocainide (MD77020?:x1_2), a benzofuran antiarrhythmic, decreased V in isolated papillary muscles and Purkinje fibers; in Purkinje fibersm!% decreased the plateau amplitude and APD. The compound antagonized digitalis- and infarction-induced arrhythmias in dogs.88-90 A report on human metabolism and disposition has appeared.91

''

E-0747 ( 3 ) was more potent than quinidine, disopyramide, lidocaine, or phenytoin. Moreover, at therapeutic doses, the compound appeared t o have low potential for cardiodepression.92 Indecainide (LY135837, g), is a potent class Ic antiarrhythmic agent93'94 with an exceptionally long half-time (52 sec) for recovery from Na' channel This compound was more potent than either aprindine or disopyramide against ouabain or Harris arrhythmias in dogs.95 Reports on its metabolism have appearedmg6 Quinacainol (PK-10139, Is) was 5 to 10-fold more potent, and longer-acting than quinidine in various animal models.97 In contrast to quinidine, there was no significant interaction with d i g o ~ i n . ~In~ dogs 15 was 40-50 times more potent than quinidine in decreasing conduction velocity throughout the myocardium.99

Antifibrillatory activity of the class I antiarrhythmic McN-4130 (16) has been investigated. It protected against VF in ischemic porcine hearts, increased ventricular fibrillation threshold (VFT) in dogs, and was highly effective in terminating acetylcholine-induced atrial fibrillation.l o o In canine Purkinje fibers 16 caused a rate-dependent decrease in V and prolonged APDloo.l o l Stirocainide (EGYT-1855, 11) also decreasepy in a use-dependent fashion and shortened the plateau of Purkinje fif$? action potential without influencing either the resting potential or the amplitude of the action potential.l o 2 Recent animal studies indicated the drug was highly effective in suppressing arrhythmias following acute infarction.l o 3

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Class 111: Update on established agents - By slowing conduction and inhibiting automaticity, class I drugs slow VT rate and control the trigger mechanisms for initiating VT. In contrast, class I11 agents act by homogeneously increasing refractoriness without slowing conduction, thus interrupting reentrant pathways and decreasing the vulnerability to VT/VF. lo4-lo6 The distinction between the antiectopic effects of class I drugs and the antifibrillatory effects of class I11 drugs, especially bretylium, has also been emphasized.l o 7 ’ l o 8 Summaries of the pharmacology and clinical use of the only marketed class I11 agents, a m i o d a r ~ n e ~and ~ ~ bretylium, ”~~ ‘11 have appeared. C l ~ f i l i u m ~ and ~ ~ ” d~ -~ s o t a l ~ l ~have ~ ~ ’ selective ~ ~ ~ class I11 properties in patients and suppress PES-induced VT with minimal side effects. Bretylium116’117 and meobentine118 were only marginally successful in patients with PES-induced sustained VT. The incidence of GI side effects and hypotension was especially troublesome with meobentine. Bretylium (30 mg/kg, infused over 24 hr) prevented the decrease in effective refractory period (ERP) accompanying acute coronary artery occlusion, thereby reducing refractory period dispersion upon reperfusion and preventing reperfusion arrhythmias.‘19 Large doses of bretylium (10 mg/kg every 12 hr for 2 days) abolished PES-induced VT in dogs with Chronic infarcts and reduced the occurrence of sudden death upon acute thrombosis. 120 Acute i .v. administration of bretylium to conscious dogs (10 mg/kg) did not prevent reperfusion arrhythmias1 and failed to elevate VFT in anesthetized dogs (10-30 mg/kg).121 A positive effect of acute bretylium (10 mg/kg, i.v.) on reperfusion arrhythmias in dogs was detected only if the area of myocardial ischemia was considered.122 The mechanism of action of bretylium remains elusive. A reduction in dispersion of refractory period123 and conduction velocity12* between ischemic and normal tissues has been reported. Clofilium, a selective class I11 agent without antisympathetic effects,12s increased refractoriness and VFT in both dogs106’126 and but was less effective than bretylium in preventing VF during acute ischemia. 123’126 Thus, the antiadrenergic effect of bretylium12’ appears to be required for optimal antiarrhythmic effects in acute ischemia models.128 At pharmacologically relevant concentrati.ons, bretylium also exerted antimuscarinic effects in guinea pig atria and bound to muscarinic receptors in rat heart.12’

’’

In isolated cardiac tissue, d,l-sotalol (10-6M

-

10-4M) increased The effects of d,l-sotalol were unrelated to f3-blockade and were mediated by decreases in background and plateau potassium current. 130 Although the class I11 actions of cj,l-sotalol could not be correlated with its antiarrhythic effects in ischemic perfused guinea-pig hearts,13* class I11 effects clearly mediated its antiarrhythmic and antifibrillatory

APD13’ and refractoriness, even in the presence of elevated K+.131

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effects in chronically I-schemic dogs.133'134 Both isomers of sotalol increased APD in vitro. 130 d-Sotalol, 2-8 mg/kg administered acutely135 or 8 mg/kg administered every-6 hr for 24 hr,136 suppressed the induction of VT in infarcted dogs, increased refractoriness and prevented development of VF in response to acute thrombosis. The p-blocking isomer, A-sotalol, had similar effects except that the PR interval was lengthened.136 Amiodarone is a fairly selective class I11 agent when administered chronically. However, superfusion of guinea pig ventricular muscle with high concentrations of amiodarone (88 pM) caused rate-dependent reductions in Vmax; 1 3 7 lower concentrations (15 pM) depressed conduction through the rabbit AV node and interfered with sinus node function by a non-class I11 mechanism.138 Short-term i.v. infusion of amiodarone (10 mg/kg/hr) in dogs with chronic infarcts was less effective than long term oral therapy (10 mg/kg/day for 24 days) in preventing VF due to acute thrombosis. 139 The enhanced efficacy of chronic therapy was accompanied by greater increases in the QTc interval, although refractoriness was not measured. Amiodarone is also a fairly potent noncompetitive muscarinic antagonist in heart tissue (K.=4-6 pM). 140 Thus, the mechanism of action of amiodarone is complex and 1probably involves a combination of metabolic, autonomic and direct effects. In rats, meobentine prolonged APD & vitro, increased refractoriness and reduced arrhythmias associated with coronary artery occlusion & viva .141 In dogs with chronic infarcts, meobentine increased VFT but did not protect conscious dogs from developing V T / W in response to PES or acute thrombus formation.1 4 2 Class 111: Recently reported new chemical entities. - A series of phenethylimidazolium analogs of sotolol were prepared. Compound CK-1649C (g) prolonged APD of isolated canine Purkinje fibers and functional refractory period of isolated ventricular muscle fibers; there was no effect on cardiac conduction, and electrophysiologically, the two stereoisomers were indistinguishable.143 Compound was orally bioavailable and antagonized PES-induced arrhythmias in dogs. The SAR leading to the discovery of a series of clofilium-like class 111 antiarrhythmics was described. Removal of an N-ethyl group from clofilium (2)a quaternary ammonium derivative, results in the formation of LY97119 ( g ) ,an agent devoid o f class I11 antiarrhythmic activity. However, LY97241 (21), the nitro congener of 111, is even more potent as a class I11 agent than clofilium.106

18

R=CL; R=NO,

20 ; 21

Agents with Mixed Activity - Propafenone has about 1/40 to 1/50 the potency of propranolol as a p-blocker;144 however, because of the large doses administered, this activity probably contributes to its clinical antiarrhythmic efficacy. 1 4 4 ' 1 4 5 Cibenzoline (22) decreased automaticity arising from depolarized membrane potentials146 and prolonged AH interval and APD in muscle of isolated rabbit tissue,147 suggesting the involvement of class I11 and IV activity. The compound is a potent sodium channel blocker in cardiac tissues in vitro 146 and has no effect

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e,148

on AH interval in dogs & suggesting that additional effects of 11 are probably of minor importance. Compound 22 is being evaluated extensively in clinical trials, and a compendium of results obtained to-date has appeared.14' Bepridil had little effect on normal canine Purkinje fiber APD or Vm , but decreased Vmax of ouabain-intoxicated were acfibers.150 The antiarrhyiYhmic effects of bepridil & companied by increased intramyocardial conduction time, QRS duration, QTc interval and refractoriness in dogs with chronic infarcts.l S 1 Thus, class I, 111 and IV activities probably contribute to the antiarrhythmic effects of this agent. The neuroleptic agent, melperone, possessed class I11 activity in isolated rabbit atrial and ventricular tissues but , especially in Purkinje fibers and the ~ e n t r i c 1 e . l ~ ~ also inhibited V Asocainol (88E-4704A, 23), has recently been advanced to clinical trials.152 This agent appeared to be a mixed class I/IV antiarrhythmic in isolated guinea pig papillary muscles. Its block of sodium and calcium channels was not s t e r e o ~ p e c i f i c .Another ~~~ example of a dual class I/IV agent is BRL-31660 (24).lS4 The combination of class I and IV mechanisms may lead to enhanced antiarrhythmic efficacy, but marked negative inotropic activity is a potential liability. A series of amino substituted steroids was investigated and CCI-22277 was found to be more active than lidocaine, disopyramide or aminosteroid Org 6001 in the rat aconitine test.155 Compound CCI-22277 was reported to be a class I antiarrhythmic with an long recovery time constant; however, additional class IV action at high concentrations was evident.156

24

22

-

Miscellaneous Agents A variety of vasodilator substances have activity against arrhythmias during acute coronary artery occlusion in dogs. l S 7 Nicorandil (SG-75, 3)shortens APD and reduces automaticity, effects mediated by an increase in K+ conductance.158 The antihypertensive agent pinacidil (26) markedly decreased ventricular ectopic beats in conscious dogs 24 hr following coronary artery occlusion;159 other vasodilators, such as hydralazine or nitroprusside were inactive. Trapidil an antianginal drug, significantly increased the amount of aconitine or ouabain needed for induction of ventricular arrhythmias in rats and guinea pigs. In isolated rabbit ventricular muscle cells, trapidil shortened APD and prolonged ERP. 160 Comprehensive reviews on the basic electrophysiology161 and therapeutic uses 162 of adenosine in supraventricular arrhythmias have appeared. This nucleoside has also demonstrated efficacy against ventricular arrhythmias in rats. 163 A prostacyclin "potentiator", nafazatrom (BAY-S6575), reduced infarct size and markedly decreased arrhythmias following acute coronary artery occlusion in rats. 164 The thromboxane synthetase inhibitor, dazoxiben decreased reperfusion VF but not occlusion arrhythmias in anesthetized dogs. 165 Moreover, additional thromboxane synthetase inhibitors, including furagrelate (U-63557A, @), markedly decreased VF upon acute coronary artery occlusion in conscious dogs. The antifibrillatory effect was blocked by indomethacin, suggesting the involvement of prostacyclin,1G6

(z),

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'CN

26

25

28

29

Phen~yclidinel~' and amiloride168 produced selective class 111 effects in isolated Purkinje fibers. Phencyclidine's effect is likely related to block of K+ currents by the uncharged amine.167 In studies investigating the role of endogenous opioids in acute ischemia, naloxone failed to protect pigs against arrhythmias associated with acute coronary artery occlusion and release. 16' The potent serotonin antagonist ICS205-930 (3)was found to have a direct, class I electrophysiological effect on the heart, and protected rats from reperfusion-induced VF and VT. 1 7 0 The contribution, if any, of its serotonin antagonist properties to this cardioprotective effect has not been delineated. Proarrhythmia - The fact that antiarrhythmic drugs can induce arrhythmias under some circumstances is now well-appreciated.171' 17* In general, the phenomenon can occur with any antiarrhythmic drug of any class. Many reports have focused on investigational class I agents, possibly because they are scrutinized carefully and used more often in patients that are debilitated and refractory to standard drugs. 173 However, an excessively prolonged QTc interval may indicate enhanced disparity of recovery times and may also be arrhythmogenic.lf4 The moderate increase in QTc that accompanies the antiarrhythmic effect of most class 111 drugs probably signifies a homogeneous increase in ventricular repolarization.1 7 5 Nevertheless, development of class I11 drugs that increase refractoriness with minimal increases in QTc would seem worthwhile. At present it is difficult or impossible to predict when and if a given patient will experience a proarrhythmic response with either class I or I11 drugs. Because aggravation of arrhythmias is of paramount importance in assessing the therapeutic potential of antiarrhythmic agents, preclinical methodology to determine the proarrhythmic liability o f new drugs will be mandatory. A few investigators have already attempted to address this issue.176y1 7 7

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Future Directions - Complex and/or frequent arrhythmias in the post-myocardial infarction population serves as an independent marker for increased 1 and 2 year mortality.178 However, no studies have yet shown that prophylactic therapy with class I or I11 agents can decrease mortality in high-risk groups. l 1 O Y 179 Carefully controlled large-scale clinical trials now being planned should address the value of arrhythmia suppression in reducing mortality in patients with potentially lethal arrhythmias. Meanwhile, the safe reduction of lifethreatening arrhythmias in high-risk patients should remain an important goal for drug development efforts. In addition, nonpharmacologic treatments such as automatic implantable cardioverter-defibrillators have been developed.leO Although these non-drug options may seem to compete with drug therapy, new drugs might actually complement such devices. Drugs that reduce the frequency of device operation or reduce current delivery could have an important impact on the design o f future electrical devices. For example, although lidocaine181 and encainide182 have been shown to increase the internal defibrillation threshold, some class I11 agents such as d-sotalol and ~ l o f i l i u mhave ~ ~ ~ the opposite effect. Finally, the availability of implantable devices may facilitate drug development efforts by alleviating ethical concerns which currently limit placebo-controlled studies of new antiarrhythmic drugs in patients with serious arrhythmias. REFERENCES

1. T. Barn, R.L. Went and J.L. Bergey i n " A n n u a l Reports i n Medicinal Chemistry," 1977, p. 39. Vol. 12, F.H. Clarke, Ed., Academic P r e s s , New York, N.Y., 2. J.T. Nobis and P. Tenthorey i n " A n n u a l Reports i n Medicinal Chemistry," Vol. 18, H-J. Hess, Ed., Academic P r e s s , New York, N.Y., 1983, p. 99. 798, (1983). 3. A.L. W i t and M.R. Rosen, Am. Heart J., 4. R. Lazzara and B.J. S c h e r l a g , Am. J. C a r d i o l . , 2,1B (1984). 5. H.A. Fozzard and J . C . M a k i e l s k i , A n n . Rev. Med., 36, 275 (1985). 6. B.N. Singh, N. Ikeda and K. Nademanee i n "Drug Treatment of Cardiac Arrhythmias," L.A. Could, Ed., F u t u r a P u b l i s h i n g Co., Mount Kisco, N.Y. 1983, p. 1. 7. J.T. Bigger, Am. J. C a r d i o l . , 53, 88 ( 1 9 8 4 ) . 8. D.P. Zips, C i r c u l a t i o n , 72, 949 (1985). 9. E.M. Vaughn Williams, J. C l i n . Pharmacol., 24, 129 (1984). 10. D.C. Harrison, Am. J. C a r d i o l . , 56, 185 ( 1 9 E ) . 11. T.J. Campbell, Cardiovasc. Res., l7, 344 (1983). 12. L.M. Hondrghem and B.C. Katzung, Ann. Rev. Pharmacol. Toxicol., 4, 387 (1984). 13. T.J. Campbell, Br. J. Pharmacol., 80, 33 (r983). 14. Symposium on the Role of Programmed Electrical S t i m u l a t i o n i n Evaluation of I n v e s t i g a t i o n a l A n t i a r r h y t h m i c Drugs, C i r c u l a t i o n , (Suppl 111, 1986. 15. J.N. Ruskin, M.H. Schoenfeld and H. Caran, Am. J. Cardiol., 52, 41C (1983). 16. J. Cameron, J.M. Isner, D. Salem, N.A.M. Estes 111, Pharmacotherapy, 5, 95 (1985). 17. H.J. J. Wellew, P. Brugada and W.G. Stevenson, Circulation, 72, 1 (1985). 18. R. C a r d i n a l , R. Savard, D.L. Carson, J.-B. P e r r y and P. Page, C i r c u l a t i o n , 70, 136 (1984). 19. J.B. Kramer, J.E. S o f f i t z , F.H. Witkowski and P.B. C o r r , C i r c . Res., 56, 736 (1985). 20. E.L. Michelson i n " P e r s p e c t i v e s i n C a r d i o v a s c u l a r R e s e a r c h , " Vol. 10, B.R. L u c c h e s i , J.V. D i n g e l l and R.P. Schwarz, E d s . , Raven P r e s s , New York, N . Y . 1984, p . 47. 21. D.S. E c h t , J.C. G r i f f i n , A . J . F o r d , J.W. K n u t t i , R . C . Feldman and J . W . Mason, Am. J . C a r d i o l . , 52, 1127 (1983). 22. S.M. Cobbe, E. Hoffmann, A. R i t z e n h o f f , J. Brachmann, W . Kubler and J. Senges, C i r c u l a t i o n , 72, 200 (1985). 1414 23. E. P a t t e r s o n , K. Holland, B.T. Eller, and B.R. L u c c h e s i , Am. J. C a r d i o l . , (1982). 24. D.M. Roden and R.L. Woosley, Pharmac. T h e r . , 23, 179 (1984). 25. M.E. Gain and M.E. Josephson i n "Drug Treatment o f C a r d i a c Arrhythmias," L.A. Could. Ed., F u t u r a P u b l i s h i n g Co., Mount K i s c o , N.Y. 1983, p. 73. 26. J.L. Anderson, C l i n . T h e r . , 6 , 125 (1984). 27. Symposium on Propafenone, Am. J. C a r d i o l . , 54, 1D (1984). 28. H . R . Kaplan, T . E . Mertz, T . J . S t e f f e and J.G. Toole i n "New Drugs Annual: Cardiov a s c u l a r Drugs," Vol. 1, A . S c r i a b i n e , E d . , Raven P r e s s , New York, N.Y. 1983, P. 133. 29. J. Morganroth, P.F. N e s t i c o and L . N . Horowitz, Am. H e a r t J. 110, 856 (1985). 30. Symposum on t h e Role of O r a l M e x i l e t i n e i n The Management o f V e n t r i c u l a r Arrhythmias, Am. H e a r t . J., 107, P a r t 2, 3A (1984).

106,

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167. G.A. D’Amico, R.P. Kline, S. Maayani, H. Weinstein and J. Kupersmith, Eur. J. Pharmacol., 283 (1983). 168. A.C. Marchese, J.A. Hill J r . , P.-D. Xie and H.C. Strauss, J . Pharmacol. Exp. Ther., 232, 485 (1985). 169. Bergey and M.E. Beil, Eur. J. Pharmacol., 90, 427 (1983). 170. F.M. Williams, A.L. Rothaul, K.A. Kane and J.R. Parratt, J. Cardiovasc. Pharmacol., 7, 550 (1985). 171. P.J. Podrid, Chest, 88, 452 (1985). 172. V. Torres, D. Flowers and J.C. Somberg, Am. Heart J., 2 ,1090 (1985). 173. J. Morganroth and L.N. Horowitz, Am. J. Cardiol., 53. 89B (1984). 174. B. Surawicz and S . B . Knoebel, J. Am. Coll. Cardiol., 4, 398 (1984). 175. D.M. Roden and R.L. Woosley, Am. Heart J., 109, 411 (1985). 176. E. Patterson, J.K. Gibson and B . R . Lucchesi, J. Cardiovasc. Pharmacol., 4, 925 (1982).

e,

m.

177. W. Schols, J . Brachmann, J . Senges, C. Herkert, E.-D. Mayer and W. Kiibler, E u r . Heart J., 6 (Suppl. l), 128 (1985). 178. J.T. Bigger Jr., J.L. Fleiss, R. Kleiger, J.P. Miller and L.M. Rolnitzkey, Circulation, 69, 250 (1984). 179. L.M. Friedman, E u r . Heart J . , 5 , (Suppl. 8 ) , 99 (1984). 180. M. Mirowski, J. Am. 2 0 1 1 . Cardiol., 6 , 461 (1985). 181. P. Dorian, J.M. Davv. E . Fain, S.M. Bach J r . and R.A. Winkle, J . Am. Coll. Cardiol., 5, 456 (1985). 182. E. Fain, P. Dorian, J.Y. Davy and R.A. Winkle, Circulation, 72, 111-384 (1985). 183. A.K. Dawson, M.I. Strinherg and J.E. Shapland, Circulation, 72, 111-384 (1985).

Chapter 11.

Pharmacological Approaches in Acute Stroke

Graham Johnson and Frank W . Marcoux

Warner-Lambert/Parke-Davis Pharmaceutical Research Ann Arbor, Michigan 48105 INTRODUCTION Stroke is the third leading cause of death in the United States today,' and yet there remains no generally agreed upon effective treatment for this devastating neurological disorder. I t has been estimated that each year 400,000 Americans suffer a stroke and two-thirds of the survivors are permanently disabled. Acute and long-term disability from stroke costs the nation over $8 billion each year. Stroke is caused by an abrupt interruption in blood supply to part of the brain, resulting in ischemia and cerebral tissue necrosis. Most often the interruption in cerebral blood flow is caused by an atherosclerotic arterial narrowing which develops progressively, but is of sudden hemodynamic significance. Another common cause of stroke is the abrupt lodging of an embolus within the cerebral circulation and its consequent, distal cerebral tissue ischemia. The treatment of acute stroke today consists mainly of individualized management dictated by diagnostic criteria and clinical predictors or outcome. Specific therapy for acute stroke includes normalization of systemic blood pressure, maintenance of vital functions and rehabilitation.5 The lack of any specific agent of proven benefit in the treatment of acute stroke is exemplified by the recent summation regarding stroke treatment, "single, best therapy : meticulous nursing care. Although it is commonly accepted that even a brief period of ischemia results in irreversible brain damage, recent experimental studies with animal models have suggested that this is not universally the case. Indeed, studies of experimental stroke in non-human primates have shown that surprisingly long episodes of cerebral ischemia can be tolerated without permanent disability and irreversible cerebral tissue injury,7'8 and, more importantly, that such tolerance is determined by the duration and degree of ischemia. ' l o ' Thus, thresholds of focal (localized) cerebral ischemia determine functional cellular activity and cerebral tissue viability.13 The clinical implications of the threshold concept are that in acute stroke pharmacological intervention which increases residual cerebral blood flow would be ex ected to lessen tissue injury and improve long-term functional outcome. l B Alternatively, treatment which enhances the brain's tolerance to ischemic conditions would also be expected to benefit the acute stroke victim. Animal model studies of brain ischemia have proposed diverse biochemical strategies for pharmacological intervention in acute stroke. Excellent reviews of such studies have been published recently. In general, the experimental findings support the pathophysiologic cascade illustrated schematically in Figure 1. ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21

Copyright 0 1986 by Academic Press. Inc. All rights of reproduction in any form reserved.

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FIGURE 1 ISCHEMIC STROKE : PATHOPHYSIOLOGIC CASCADE Thrombo-Embolic Cerebral Artery Occlusion Focal Cereb a1 Ischemia

f

Energy

.) Depletion/N uronal

e

Inactivation

I

I I

tlL&li

t[KTIO

I

t[Cal"Ii

t

I

t[y,

t[&IO t Interstitial

t

f t Glial swelling Membrane Phospholipase Local metabolism Injury Activation Edema Vasoconstriction Free fatty acid Liberation I Membrane t injury/ Permeability

Arachi! r onic Acid Metabolism

t

Prostaglandins Thromboxanes Free radicals

+

Local metabolism Vasoconstriction

Membrane injury/ Permeability Vasconstriction

I

t

Leuko triene s

.)

Membrane injury/ Permeability Vasconstriction

Abbreviations : f [ l o = increase in the extracellular concentration )f potas ium (K'), water (H20), and neurotransmitters = increase in the intracellular (Nt); ![]i Joncentration of lactate (Lac) and calcium (Ca++). Note :

Focal Cerebral Ischemia refers to a localized area )f reduced blood flow sufficient to impair cerebral Arrows indicate increases in or tissue function. production of the species o r event noted and progression of ischemic injury.

From the above simplified scheme, possibilities for pharmacological intervention in acute stroke are suggested. In the section which follows, an attempt has been made to review such possibilities briefly by pharmacological mechanism of action and emphasizing the supportive experimental and clinical data where possible. MODIFIERS OF CEREBRAL METABOLISM A s is implied in Fig. 1 and might be inferred logically in the treatment of acute stroke, a pharmacological reduction in the ischemic cerebral tissue's metabolic demand might be expected to protect against irreversible injury, Therapies which exemplify this approach are summarized below. sufficient to depress brain metabolism has been Hypothermia proposed as beneficial in stroke.lg Hypothermia also slows cerebral perfusion by increasing blood viscocity and can therefore have detrimental effects. * O

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Phamacological Approaches i n Acute StrokeJohnson, Marcoux

111

-

Barbiturates such as phenobarbital, have been shown to inhibit cellular glycolysis and hence cerebral metabolism. Although early studies were suggestive of a benefit in the treatment of stroke,22 cardiorespiratory liability resulting from the high dose levels required have made this a last choice treatment, 23 Anticonvulsants - have also been proposed as treatments for acute stroke on the basis of their activity as inhibitors of cerebral metabolism. 2 4 In particular, phenytoin has shown protective effects during experimental cerebral ischemia, but clinical data in acute stroke have not been reported. 25 ATP Modifiers - The extreme susceptibility of the brain to ischemia results from the very limited reserves of the high energy phosphates, ATP and phosphocreatine, Therapeutic efforts to maintain the levels of these high energy intermediates have taken several paths. The infusion of ATP itself in dogs has been reported not to benefit ischemic tissue. 26 However, in animal models, the beneficial effect of acute administration of phosphocreatine in combination with creatine pho~phokinase~ and ~ chronic administration of cyclocreatine phosphate (1 ) has been reported.28 A number of agents have also been reported +

U

to inhibit the decline of neuronal ATP levels in a h poxic o r ischemic (2), dih drobrain. These include n i ~ e r g o l i n e , ~pJ;idoxylate& ~ dihydroergocristine, 3 J and ergotoxine, 31 vindeburnol (RU24722) (3), In rat cortex, indoramin (5) recently the substituted quinoline (4).'4 at subhypotensive doses increased the rate of ATP synthesis ,31 ' 3 5 Naftidrofuryl (6) was also shown to both stimulate synthesis and slightly inhibit Fhe utilization of ATP. 3 1

(7HS" - N/NTu

OR

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Oxyhemoglobin Destabilizing Agents - The partial pressure of oxygen is influenced by the rate of available in ischemic tissues dissociation of oxygen from hemoglobin. 36 In ischemic tissue, the slowed clearance of the metabolic endproducts, (202, and lactic acid combine with endogenous 2,3-diphosphoglycerate to destabilize the oxyhemoglobin complex and make oxygen more readily available to the tissues. Efforts to develop agents which augment this process have also been reported. A series of quinone derivatives, exemplified by (7), have been disclosed as enhancers of blood 2,3-diphosphoglycerate Gvels .37 0

7 -

Although not operating through a modification of diphosphoglycerate levels, xanthone derivatives ( 8 ) have been reported, which interact direct1 with the oxyhemoglobk complex and bring about destabilization. 3 8 Substituted triazines (9) have also been claimed to increase the partial pressure of free arterial oxygen. 39

-

Blood Substitution The appeal of this approach is the reduced viscosity and hence easier penetration of the ischemic foci by the oxygenated carrier. The major focus of blood substitution research has been on Fluosol D A , an emulsion of erfluorodecalin and perfluorotripropylamine. Clinica140 and animal4!' 4 2 studies using ~ shown some Fluosol DA alone or in combination with m a n n i t 0 1 ~have A related approach to cerebral oxygenation beneficial effect. utilizes the perfusion of an oxygenated fluorocarbon nutrient emulsion The salvage of severely through the cerebrospinal pathway. 4 5 ' 4 5 ischemic tissue by this technique has been reported recently in a cat model. 4 6 The generation of neohemocytes, prepared from purified human hemoglobin and 2,3-diphosphoglycerate encapsulated in a membrane of The small phospholipid and cholesterol, has been reported. 47 particle size and good in vivo toxicological profile in rats, should make this a viable candidate for blood substitution trials in experimental stroke. Additional simplification of this concept, using iron tetraphenylporphyrin complexes has also been disclosed. 48 CEREBRAL VASODILATORS Prompt return of cerebral blood flow would be expected to limit ischemic tissue necrosis. However, nonselective agents may exacerbate ischemic damage either by diverting blood to nonischemic brain areas, the so called 'steal syndrome,' 4 9 , 5 0 or by causing hypotension through peripheral vasodilation. Although beneficial reports of cerebrovasodilators in stroke are uncommon, 5 1 vincamine and papaverine have been reported active in experimental studies. 52 Cerebrovascular-selective calcium channel antagonists have been

Chap. 11

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113

described. 53 Of these flunarizine and nimodipine have been reported to be active in animal models of hypoxia and ischemia.54’55 Clinical studies using nimodipine in thromboembolic stroke remain inconclusive; however, this agent has shown efficacy in the treatment of subarachnoid hemorrhage-induced cerebral vasospasm . 56 INHIBITORS OF NEURONAL INJURY Proposing, as the threshold concept suggests, that an ischemic penumbra or area of compromised yet viable brain may dominate in acute stroke, 57 ’ s 8 pharmacological intervention to prevent this tissue from progressing to irreversible injury would seem warranted. 59 Several strategies have been proposed, based on experimental studies on cerebral ischemia pathophysiology . Antioxidants - A significant body of evidence has established that during an ischemic event, free radicals such as superoxide anion, hydroxyl radical, o r lipoperoxides are generated by a variety of mechanisms. 6 o ’ 6 1 ’62 Free radical scavengers have been investigated in experimental stroke models. These agents would augment endogenous antioxidan t syst e m s . Mannitol, 6 3 vitamin E (to~opherol)~~, methylprednisolone, 65 ubiquinone, (coenzyme Q) ,66 a component of the

mitochondria1 electron transport system, its derivative idebenone (CV 2619) (lo), 67 and 1,2-bis(nicotinamide)propane (AVS) ,6 8 have all been reported to function in part as free radical scavengers and inhibit lipid peroxidation. Several phenolic species (11)69 ( 12)70 have also been claimed to act as antioxidants in the t r e a 5 e n t o f hypoxic conditions. Iron Chelators - The presence of iron in a wide range of enzymatic systems, such as hemoglobin and ferritin, make free iron readily available under ischemic conditions. This iron is thought to catalyze the generation of free radicals from reactive oxygen species. 71’72 Stroke therapy based on the chelation of free iron has received scant attention. However, a study of deferroxamine (13) in rats has confirmed the potential use of this approach in brain resusxtation. 73

OH

OH

-

OH

13

Excitatory Amino Acid Antagonists - Following an ischemic insult, the massive release of glutamate and aspartate from cerebral tissues has been confirmed both & vitro74 and in vivo.75’76 These neurotransmitters have been shown to contribute to neuronal cell death possibly through deplorization induced edema. 77

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Recent studies using 2-amino-7-fhosphonoa specific heptanoic acid (7APH) (14), 7 8 ' N-methyl-D-aspartate TNMDA) receptor 0' 'OH NHZ antagonist, have shown that by prior 14 intracerebral administration a protective effect against hippocampal injurT is observed in animal models following a temporary and hypoglycemics2 insult.

"',p/VVy

-

Following the observation that the opiate antagonist naloxone Opiates. could unprove the symptoms of stroke in both man83 and gerbils,84 many subsequent studies, including clinical trials have appeared which have both supporteds5 and refuted86 these original findings. Later studies have shown that n a l t r e ~ o n '8s e ~ ~ and levallorphanag also exert a protective effect in animala7 and human trials.89 The mechanism by which naloxone and associated opiates exert their protective actions is not known. Stimulation of selected brain motor centers may be responsible for the apparent neurological improvement seen in both animals and in man.g0 Given the benefit of both naloxone and naltrexone in prolonging poststroke long-term survival in cats, 87 the observation that opiate antagonists reverse opiate induced leucocyte chemotaxisgl and superoxide releaseg2 may be of relevance.

A central role for the Kappa receptor is suggested by recent studies which demonstrate that dynorphin 1-1393'a71 9 4 and the Kappa agonist U-50,488E ( 15)95 afford protection from cerebral ischemia in selected animal modas. It is of interest to note that the Kappa antagonist WIN 44,441-3 (16) has also been shown active in improving the neurologic recovery from ischemic spinal cord injury. 96 Chemotaxis Inhibitors - It has been shown that by four hours following ischemia, leucocytes become concentrated in areas of low blood flow, These recruited leucocytes may, during the critical early hours to the of ischemia, contribute H y 4 % o " evolution of neuronal damage. 9 7 Inhibition of leucocyte migration HO within areas of compromised CNS 17 tissue o r inhibition of resulting phagocytic activity might reduce of an initial the progression ischemic insult. Distinct from known inhibitors of arachidonic acid metabolite induced chemotaxis a tripeptide inhibitor of leucocyte pha ocytosis (lJ) has also been been developed by the Pasteur Institute. 9 f

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Phamacologlcal Approaches in Acute Stroke Johnson, Marcoux

115

INHIBITORS OF DAMAGING ISCHEMIC METABOLITES A s the schematic pathophysiologic cascade (Fig. 1) suggests, activation and/or release of inhibition of certain metabolic pathways in ischemic tissue can lead to the accumulation of active metabolites which might exacerbate the progression to irreversible injury. Prostaglandins - can be vasoconstrictive and detrimental (PGF2 ) or vasodilatory and beneficial ( PGfYz) in ischemic tissue. 99 Inhibition of the cyclooxygenase pathway may prevent the accumulation of vasoconstrictive prostaglandins and thromboxanes (TXA2), and therefore, prevent further ischemia. In general, however, both cyclooxy enase 18 COOH inhibitors100’l o l and prostacyclin1‘j2’ l o 3 have shown controversial results in experimental stroke models. Indeed, recent clinical trials with prostacyclin infusions in acute stroke have not been promising. l o 4 Initial studies with a thromboxane synthetase inhibitor, dazmegrel (UK 38,485) (g), have also been discouraging. l o 5

-

Leukotrienes - are produced from arachidonic acid via the lipoxygenase pathway. These compounds are, in feneral, vasoconstrictive, frequently increase vascular permeabilit lo6’ O7 have recently been shown to accumulate in ischemic brain1 and may adversely affect outcome from acute stroke. The activity of lipoxygenase inhibitors in stroke models has yet to be reported, however, several compounds, including BW755c (19)lo9 and nafazatrom (20)’1° have shown promise in models of myocardialischemia .

B,

aNH2 I

OTHER APPROACHES

-

have been An tiedema Agents proposed for some time a s an approach to the treatment of acute stroke. Indeed, work with experimental models of stroke has demonstrated the edema in the importance of pathogenesis of ischemic cerebral injury. ’ However, steroid and osmotic diuretic therapies have shown inconsistent activity in acute cerebral ischemia. l 4’ l 5 A recent report suggests that cyclooxygenase and lipoxygenase inhibitors may

A

O + q H

21 -

116 -

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- Pharmaoadynamic Agents

Bristol, Ed.

substitute for o r be additives to steroid therapy for cerebral edema. 116 A series of cerebral antiedema compounds has recently been reported. (21).11’

-

Fibrinolytic Agents Fibrinolytic removal of a clot with subsequent tissue reperfusion is an appealing solution to the problem of a thromboembolic stroke. However, this approach may lead to hemorrhagic complications. This not withstanding, small clinical studies using the nonselective plasminogen activators, urokinase and, less frequently, streptokinase, have been reported. l I 8 ’ A recent study of the embolus selective tissue plasminogen activator (TPA) in a rabbit embolic stroke model has yielded encouraging results. 120 New heparinoid drugs which lack the bleeding risk of those presently available have also been reported. 1 2 1

-

Nootropic or cerebroactive drugs have been reported to be active in animal models of brain hy oxia and ischemia. 11* Limited experimentalE3 and clinical124 data have suggested improvement after treatment with the prototypic nootropic, piracetam

a,,

0

I CH,

22 -

fiNHz

0

(22)Hemorrheologic Approaches

-

to

the treatment of acute stroke have utilized pharmacological and nonpharmacological means by which to decrease blood viscocity and thereby improve residual cerebral blood flow. Hemodilution has been shown effective as a treatment for acute stroke. 125 ,126 Pentoxiphylline (23), which improves blood flow by inireasin red blood cell deformested as a ability, 12% was treatment for stroi:FY;s and is now in clinical trials.

A-y; O

23

N

N

Enhancers of Neuronal Plasticity - Gangliosides, a class of complex biological molecules which belong to the glycolipid family, have been known for some time to potentiate axonal sprouting after peripheral nerve injury, and more recently such findings have been extended to the CNS. 129 GMl , a specific monosialoganglioside, has been shown to reduce cerebral edema in an animal model of brain injury130 and to improve neurological outcome in a small clinical trial of stroke patients.131

-

arising from anaerobic glucose metabolism has been Lactic Acidosis proposed to play a role in ischemic cerebral injury. 132’133 Substitution of glucose by 1,3-butanediol, a ketone substrate, has been reported to be beneficial in stroke models.134 CONCLUSION From the forgoing survey, it is apparent that despite the breadth of pharmacological approaches which have been examined for the treatment of stroke, no single effective therapy has yet emerged. However, from the rapid progress currently being made in the understanding of stroke pathophysiology it is probable that effective strategies for stroke therapy will be identified in the next few years.

Chap. 1 1

Phamacological Approaches in Acute Stroke Johnson, Marcoux J l References

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3. 4. 5. 6. 7.

8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

20. 21.

22.

23. 24. 25. 26. 27. 28. 29. 30. 31.

32. 33. 34. 35.

36. 37.

38. 39. 40. 41. 42. 43, 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54.

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alla as.

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-

u,a.

x.

z.

-

u.

118 5. 5. M. M.

77. 78 * 79 *

5.

81 82.

9

83.

M. 85. 86 87.

I

88. 89. 90. 91 92. 93. 94. 95. 96. 97.

I

98. 99 * 100. 101. 102. 103. 101. 105. 106. 107. 108. 109. 110.

111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125.

126. 127. 128. 129. 130. 131. 132.

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1, 3 (1985). 0. Kompala and C. F. Babbr. Ann. Emrg. Mad.. 14, 509 (1985). Hauptman. 0. Nelson. 0. F. Wilson and M. E r e c l z k a , Brain Rer., 304. 23 (1984). Errcinrka. 0. Nelson. 0. F. Wilson and I . A. Silver. Brain Rer..gA, 9 (1984). H. Hagberg, A. Lehmnn. M. Sandberg. 8. Nyrtrom.1. Jacobson and A. HambOrpOF. J. Cereb. Blood Flow Metab.. 5, 413 (1985).

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Section I1

0. Aurt, L. A. Morehoure and C. E. Thomas, J. Free Radicals B i o l . Mad..

Rothman. J. Neurorci.. 4, 1884 (1984). B r i t . Pat. 2104078. March 2. 1983. M. N. Perkinr, T. W. Stone, J. F. C o l l i n s and K. Curry, Neurorci. Lett.. 23, 333 (1981). R . P. Simon. J. H. Swan. 1. G r i f f i t h r end 8. S. Meldrum. Science, 226. 8 5 r ( 1 9 M ) . 8. Meldrun, M. Evens, T. G r i f f i t h r and 5 . Rodger, Br. J. Anaesth..7f, 44 (1985). T. Wielock, Science, 681 (1985). 0. 5. 8arkln end V. Horobuchi. Lancet. 2. 272 (1981). V. Horobuchi, 0. 5. Barkin and 5. K. Woo, Science, 215, 69 (1982). J. Jabaily and J. N. Oavir, Stroke. E , 36 (1984). R . J. F a l l i r . M. Fisher and R. A. Lobo. Stroke. y. 627 (1984). 0. S. Baskin. H. Kuroda. V. Horobuchi and N. M. Lee, Neuropeptides. 5 , 307 (1985). US. Pat. 4459299. July 10. 1984. N. Hrndr, M. Matruntoto. M. Nakmura, 5. Voneda. K. Kimura. Y. Sugitani. K. Tanaka, 1. Takano and T. KaMda. J. Cereb. Blood Flow Metab., 5, 469 (1985). R. M. Levy. M. Strykar and V.-Horobuchi. L i f e Sci., 33 Suppl . 1. 763 (1983). M. R. Ruff, 2. M. Wahl. S. Mergrnhagen and C. B . P e r c Neuropeptides. 5 . 363 (1985). C. 0. Sinpkinr, N. Ives. E. Tat@and M. Johnson, L i f e Sci., 37. 1381 (1985). D. 5 . Earkin. V. Hosobuchi. H. H. Loh and N. M. Lee. Nature.-=, 551 (1984). Eur. Pat. 147194. July 3 , 1985. A. H. Tang. L i f e S d . , 37, 1475, (1985). A. I.Fadrn and T. P. Jzobs. Neurology. 21. 1311 (1985). J. M. Hallbeck, T. Obrenovitch, K . Kumaroo, C. Thompson and 0. R . Leitch. Philos. Trans. R. SOC. Lond., 304. 177 (1984). World Pat. 8400108, Jan. 19. 1984. M. A. Morkowitz and S. R . Coughlin. Stroke, g. 882 (1981). T. M. Louts. 0. W. Sonus. 0. G. 5 . Oavir and A. E. Kopelman. IRCS Mad. Sci.. 12, 122 (1984). R. 0. Boulu. M. Plotkine. G. Gueniau, M . Softer and N. Wierrtsperger. Pathol. m o l . , 30, 278 (1982). I . A. Awed. J. R. L i t t l e , F. Lucas, V. Skrlnska, R. Slug9 and R . P. Lesser, Stroke, 203 (1983). W. Van Den Kerckhoff and K-A Horsmann, Stroke. 2,724 (1983). J. F. Martin. N. Hamdy, J. N i c h o l l . N. Lewtas. U. Bergrall, P. Owen. 0. Syder and A . Middlebrook, N. Eng. J. Mad., 312, 1642 (1985). N. A. M o u G r i j . J. R. L i t t l e . V. Skrinrka. F. V. Lucas. J. P. Latchaw. R . M. Slugg and R. P. Lesser. J. Neurosurp. 6 , 1107 (1984). 1. 5. Wolf;,3. Neurochem.. 38. 1 (1982). K. L. Black and J. T. Hoff, S n a l s o f Neurol.. 18, 349 (1985). M. A. Morkowitz, K. J. Kiwak, K. Hekimian and LyLnvine. Science. 886 (1984). 5. R. J o l l y and 8. R . Lucchesi, Am. Heart. J.. 06. 8 (1983). M. J. Shea. J. J. Murtagh, S. R. J o l l y , G. 0. Abrams, El. P i t t and B. R. Lucchesi, Eur. J. Pharmacol.. 102. 63 (1984). H. M. Payan end J. H. Conrad. Stroke, 4. 194 (1977). I . Klatro. J. Neuropath. Exp. Neurol., 26, 1 (1967). J. H. Garcia, Stroke, g ,5 (1984). A. M. 8r-r. K. Venada and C. R. West. Neurosurgery. 5. 149 (1980). J. C. de l a Torre and J. W. Surgeon, Stroke, 1. 577 (1976). J. L. Ambrur. J. Halpern, H. Baerwald and R. J. R. Johnson, Lancet. 2, 148 July 20. 1985. Eur. Pet. 160891, Oct. 13, 1985. G. H. Barlow. Prog. Cardiovascular. Dis., 21. 315 (1979). 6. V. A. K. Sharme. G. Cella. A. F. P a r i s i y n d A. A. Sarahara. N. €1191. J. Med., 306. 1268 (1982). 1289 (1985). J. A. Zivin. M. Flrher. U. OeGirolami, C. C. Hemenwry and J. A. Starhak. Science,=O, H. Ten U t e , C. P. Hrnny, H. R . B u l l r r . J. W. Ten Cate and H. N. Magnani. Ann. N e u T . . 268 (1984). A. Spagnoli and G. Tognovi. Drugs. 26. 44 (1983). M. Nikolova, R . Nikolova and 0. Milanova. Math. and Find. Exptl. Clin. Pharmacol., 6. 367 (1984). M. Bogarrt in "Drug Treatment and Prevention i n Cerebrovascular Disorders," G. Tognovi and S. G a r a t t i n t , Eds.. E l r e v i r r / N o r t h Holland Biomedical Press. Amsterdam. New Vork. Oxford, 1979, p. 235. J. H. Wood and 0. 8. Kee, Current Concepts of Cerebrovascular OiselsO, Stroke. 20, 7 (1985). T. Strand, K. Arplund. S. Erikron, E. Hagg, F. Lithner and P. 0. Wester. Stroke. g, 980 (1984). R . Schubotz and 0. Muhlfellner, Cur. Mad. Res. Opin., 0 . 609 (1977). J. F. Hartman, R. A. Backer, and M. M. Cohen. Neurology. 27. 77 (1977). U. J . Freed. L. d r Medinaceli and R. J. Wyatt. Science, 1544 (1985). 5. E. Karpiak and 5. P. R h a d i k . J . Heurorcience Res., 12, 485 (1984). 5. Bart, M. 0. A l b i r z a t i , M. Sbacchi, L. F r a t t o l a and MrMaosarotti, Strokn 16 899 (1985). R . E. Qerr i n "Cerebral Hypoxia and I t s Consequences. I' 5. Fahn, J. N. Oavjs-iAd L. P. Rowland. Eds.. Adv. Neurol., @. 195 (1979).

a,

-

-

z,

a.

B.

g,

SECTION 111

- ChemotherapeuticAgents

Editor: Frank C. Sciavolino, Pflzer Central Research, Groton, CT 06340 Chapter 12. Antimicroblal Drugs

- Cllnical Problems and Opportunltles

Thomas D. Gootz, Pfizer Central Research, Groton, CT 06340

-

Introduction Future opportunities for product development in antimicrobial chemotherapy will be guided as much by the economics of therapy as by the perceived need for improved antimicrobial coverage.' Current economic trends indicate that incremental improvements in spectrum or potency will not be sufficient to guarantee the profitability of new agents.l.2.3 Indeed, new antimicrobials will have difficulty getting placed on the hospital formulary unless they demonstrate clear economic and therapeutic advantages."' A significant advantage would involve the use of some new compounds as single agents, replacing expensive combination therapy with less potent compounds.8~9In order to accomplish this, new antimicrobials would have to have an outstanding spectrum, including many of the organisms listed in Table 1, that have proven difficult to treat with currently available agents. The purpose of the current review will be to describe several of these organisms and to discuss their mechanisms of antimicrobial resistance where they are known. Effort will be made to describe new agents that have shown promising activity against these clinical pathogens. The microorganismsreviewed have been chosen based upon the following observed clinical trends: a) drugresistant, Gram-positive cocci have made a resurgence in causing nosocomial infections; b) infections involving enteric bacilli like Enterobacter, Serratia and froteus often remain refractory to therapy with broad spectrum drugs; c) Gram-negative non-fermenters like Pseudornonas and Acinetobacter remain multiresistant; and d) atypical mycobacteria and fungi are increasing in frequency in infections involving immunocompromised patients.5~10,11~12

-

Importance of Gram-posltlve Cocci Gram-positive cocci continue to be extremely important in causing nosocomial infections in the United States.10~14Staphy/oc~~cus aureus remains an important pathogen in primary bacteremia and with cutaneous and surgical wound infections.10~13The importance of S. epidermidis is growing as a pathogen in intensive care units and with infections in imrnunocompromised patients.10114~15The role of the staphylococci in nosocomial infections is not surprising, consideringtheir ubiquitous nature in the environment. From 50 to 90% of hospital personnel are nasal carriers of S. aureus, and S. epidermidis is present on the skin of >90% of the general population, making the reservoir for infection extremely large.10116-19The outcome of infection is influenced by the overall susceptibility of these organisms to antimicrobial agents. While the majority of staphylococci in the hospital environment are resistant to penicillin due to the elaboration of penicillinase, more alarming trends are occurring with regard to their susceptibility to newer agents.20121 Staphylococci as well as other Gram-positivecocci, can demonstrate decreased susceptibility to a wide variety of beta-lactams by either a tolerance mechanism or some intrinsic change such as altered penicillin binding proteins (PEPS).Tolerant organisms, by definition, show a dissociation between the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) to beta-lactams."25 In this sense, tolerance does not represent a form of true resistance since in the tolerant strains examined to date, the MIC has been essentially the same as observed in routinely susceptible isolates.20 While tolerant strains maintain a normal MIC to beta-lactams. some block exists in the series of events leading to bacterial lysis. This blockade is most likely at the level of release and activation of the cell's autolytic enzymes.26-28 Several investigators have shown that the detection of tolerance in vitfo is highly dependent upon the culture and testing conditions employed.*9-31 While tolerance has been identified in over twenty species, the clinical significance of the phenomenon remains uncertain.32333 ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21

Copyright 0 1986 by Academic Press, Inc. All rights of reproduction in any form resaved.

120

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Table 1. Cllnlcal Pathogens Often Resistant to Antlmlcroblals ~

Pathogen Staphylococci Meth-R

Ampiclllin

~~~~~~

Antlmlcroblal Tobramycln Cefoxltin Cefotaxime Norfloxacin

>64

32

>64

x4

8

4

16

x4

64

16

Pseudomonas aeruginosa

>64

4

x4

64

4

Acinetobacter

>64

16

>64

64

16

Enterobacter cloacae

>64

4

3 4

0.5

0.5

Serratia marcescens

x4

16

64

0.5

4

fntermci

aYinimal inhlbitory concentratlon required to inhibit growth of 90% of boiates, from ref. 168.

A subject generating much greater concern in the clinic, involves the potential spread of methicillin-resistant staphylococci (MRS). High-level methicillinresistance (MR) can be rapidlydistinguished from the tolerance phenomenon, in that MR is associated with high-level resistance to semisynthetic penicillins and cephalosporins. The incidence of MRS in the United States has been highly variable between institutions,being highest in large teaching hospitals.5 From a few to 50% of S. aureus infections are caused by methicillin-resistantisolates.34-37 The frequency of S. epidermidis isolates that are MR is reported to be even higher.5#3*JsAs might be expected, many patients infected with MRS are immunocompromised in some way and are least able to resolve the infection, necessitating aggressive antimicrobial therapy.5,10,40 Since many MRS are also resistant to aminoglycosides, therapy usually consists of vancomycin.10 With the suggestion of an increase in the frequency of MRS in some institutionsand the limited choice of therapy currently available, attention has turned to developing safe and effective agents against these pathogens. In order to evaluate the clinical need for developing such effective new agents, a full understanding of the mechanism and potential for further spread of this resistance must be considered. Evidence suggests that the overall incidence of nosocomial infection with staphylococci may not actually increase in institutions where MRS have become endemic.34 MRS strains may simply replace endemic strains that are susceptible to methicillin in the institution.34 Such selective pressure is likely due to the increased use of beta-lactamase stable penicillins and cephalosporins occurring in contemporary clinical practice. The magnitude of the problem can best be predictedfrom the mechanism of MR which has been recently elucidated. Resistance to methicillin is intrinsic and is not due to the production of penicillinase.~~ Some confusion has arisen in the literature concerning the role of the penicillinase plasmid in MR. It was recognized early that the in vitro transductionto MR in S. aureus was dependent upon the recipient strain containing a penicillinase plasmid.42 This increased frequency of transduction to MR could also be accomplished if the recipient was previously lysogenized by prophage.43 This dependence upon the penicllinase plasmid for successful conversion to MR is misleading since the structural mec gene is believed to be located on the chromosome in S. aureus.42 This dependence on the penicillinaseplasmid for establishment and expression of MR in S. aureus laboratory isolates may have some relevance in clinical isolates as well. Although the majority of resistant strains in one study contained the penicillinase plasmid, in 80% of the clinicalstrains studied the plasmid could be eliminated from the isolates and MR was maintained.44 It is clear that MR is not due to elaboration of penicillinaseand the rnec gene is not located on plasmids encoding penicillinase. However, the presence of these plasmids andlor prophage may play

Chap. 12

Antimicrobial Drugs-Clinical Problems/Opportunities

Gootz

some role in making a methicillin susceptible cell accept the rnec determinant.43144Studies are in progress to identify the locus of the rnec determinant on the S. aureus chromosome and study the nature of its transfer in this species.45 Since the spread of MR is not due directly to an R factor, an understanding of the expression of this intrinsic resistance plays an important role in predicting its potential clinical impact. MR is a heterogeneous form of resistance in most strains in that under normal in vitro culture conditions of 37OC, only a portion of the population expresses resistance.44 The percentage of cells that are resistant can be raised to nearly 100% under culture conditions of 3OoC or in medium containing 5% NaC1.45-49The heterogeneous nature of MR is a stable trait since resistant populations will return to a mixed phenotype when cultured under conditions that do not favor expression of the resistance.44 Consistent with this phenomenon has been the finding that expression of low affinity PBPs correlates with the occurrence of MR. Beta-lactam susceptible strains of S. aureus and S. epidermidis normally contain four PBPs that can be detected in polyacrylamidegels, following labelling of membrane preparations with 1°C-penicillin G.55 It is believed that PBPs 2 and 3 are the essential binding proteins in S. aureus that are responsible for cell growth.55 It is believed that PBPs 2 and 3 are the essential binding proteins in S. aureus that are responsible for cell growth.55 Resistant strains have been found that contain variants of these lethal proteins and these resistance-associated PBPs have low affinities for methicillin and many other betaIactams.",45,53,54,57,5* The low affinity PBP most commonly identified in s. aureus has a molecular weight of 78,000 daltons and migrates on SDS polyacrylamide gels very close to PEP-24453 Labelling studies using whole cells indicated that the low affinity protein PBPQ' was not saturated until levels of methicillin reached 1 mglml, which correlated with a similarly high MIC to the drug.54 The "normal" PBPs in such a resistant cell are saturated at concentrations up to 1,000-fold below this level, therefore, PEP-2' apparently can act independently in carrying out all the necessary functions associated with normal cell division.54 As would be predicted, culturing the resistant S. aureus cells at pH 5.2 both eliminated expression of PBP-2' and methicillin resistance.54 This mechanism of intrinsic resistance seems even more complex in that both individual PBPs other than PBP-2' and multiple changes in several PBPs have been associated with resistance to beta-lactams.~~59 Beta-lactams have also been shown to be effective inducers of high levels of the low affinity PBPs.59160 Thus, in strains of staphylococci, there are low affinity PBPs that are responsible for conferring intrinsic resistance to a wide variety of structurally diverse beta-lactams. Given that some beta-lactams have been shown to induce higher levels of these low affinity PBPs in the cell, is there a rationale for discovering new beta-lactams that are effective against these nosocomial pathogens? A number of new beta-lactams have been developed that show improved activity against MRS, presumably due to their increased affinity for the resistance associated PBPs. Cefmetarole is a broad spectrum, cephamycin-type antibiotic with cyanomethylthioacetamide and methyltetrazolylthiomethyl radicals on the 7 and 3 positions, respectively (Table 2). Although some degree of activity is claimed against MRS, studies with PBPs of these organisms indicate that the low affinity PBP-2' is saturated by cefmetazole levels one hundred-fold above the MIC.61 A similar minor improvement in in witro potency against MRS is seen with imipenem (Nformimidoyl thienamycin (l),in which published MICgOvalues generally range between 8 and 64 pglm1.62-64 Strains of S. epidermidis have been shown to express an inducible form of resistanceto imipenem that is distinguishable from PBP changes.65 It is not yet clear whether this phenomenon limits the efficacy of the drug against these organisms in vivo.

1

2

3

122

Section I11

- Chemotherapeutic Agents

Sciavolino, Ed,

Certain members of the penem class of antibiotics have shown promising activity against MRS. While sulfur-linked compounds at C-2 of the penem nucleus like SCH-34,343 (2) have poor activity against MRS, some carbon-linked compounds demonstrate significantly improved potency in vitm.64,88167 As shown in Table 2, the reported MICeovalues for FCE-22,101 (3) against MRS are , h a s undergone extensive biological evaluation.6l Also studied was a s e r i e s of 7-arylglycyl cephalosporins (10) having e t h e r substituents at t h e 3-positi0n.6~ In

F$fp!

Coon

-5

A=

-cn,

x=

II

i X=

COOH

Chap. 13

B-Lactarn A n t i b i o t i c s

Dunn

133

general, increased aliphatic chain length of t h e e t h e r resulted in increased gram-positive but decreased gram-negative activities. Also, increased chain length led to decreased o r a l absorption, though s o m e t i m e s results w e r e mixed. C G P 33098A another new orally a c t i v e compound, has a s e c t r u m of a c t i v i t y Only 20-25% was similar t o t h a t of FK027 but may b e more readily excreted in t h e urine of rodents. The p-hydroxyphenylglycyl derivative BM Y 28100 (4) showed in v i t r o activity comparable to t h a t of c e f a c l o r and superior to ~ e p h a l e x i n ~ s . 6 4 However, i t was m o r e susceptible to l3-lactamases. Pro-drug forms of several parenterally a c t i v e cephalosporins have been reported. K Y-109, a bifunctional pro-dru was well-absorbed orally65 as w e r e t h e pivaloyloxymethyl esters R 0 1 5 - 8 0 7 5 ~ 6 - ~ 8and ME I207.69*70 Additional publications a p p e a r e d o n t h e pharmacokinetic and antibacterial properties of t h e pro-drug cefuroxime axetil.71 Laborator or clinical studies also w e r e published on cefixime (FK027),72 DN-9550)3 YM-13115,74y75 FCE 20635,76 L-IO5,77 SK&F 88070,78 BM Y -28 1 42,79-81 cef pi ramide ,82983 and cef pirome .84,85

(u),

Penicillins - Few reports of new penicillins appeared in 1985. Interest h a s continued in t h e novel and potent 6a-formamidopenicillin BRL36650 (131.86 Two synthetic chemical publications reported t h e introduction of t h e 6a -formamido function into t h e penicillin molecule.87,88 A new, broad spectrum penicillin VX-VC 43 was reported to b e superior to piperacillin, b u t was not s t a b l e to l3-lactamases.89 Comparison of t h e antimicrobial properties of temocillin s i d e c h a i n epimers revealed t h a t t h e R-isomer is t w i c e as potent as t h e S-isomer against aeruginosa, however, epimerization t a k e s place rapidly even under normal bioassay conditions.90 One review of t h e in vitro antibacterial activities of temocillin a ~ p e a r e d . 9 ~ Penems - The synthesis and antibacterial roperties of a series of novel penems typified by compound (14) was reported.82 This compound displayed a broad spectrum of a c t i v i t y against both g r a m p o s i t i v e a n d gram-negative b a c t e r i a including B. fragilis, b u t not Pseudomonas. T h e novel penem, FCE 22101 inhibited t h e growth of most Enterobacteriaceae but was less a c t i v e than c e f o t a x i m e and c e f t a z i d i m e against t h e s e 0 r g a n i s m s . ~ 3 Reviews appeared on t h e antibacterial activity of a series of 2-(substitutedthiamethyl) penems,94 and on t h e potent, broad spectrum penem Sch 34343.95-97

(e),

-

Carbapenems The synthesis of several new carbapenem antibiotics structurally related to thienamycin was described including t h e novel 9-methoxythienamycin (161.98 These derivatives, however, w e r e significantly less a c t i v e t h a n thienamycin in vitro. Several additional members of t h e pluracidomycin family of

134

S e c t i o n I11

- Chemotherapeutic Agents

S c i a v o l i n o , Ed.

was carbapenems were isolated from Streptomyces.99 Pluracidomycin A2 (17) reported t o b e t h e first example of a sulfinic a c i d isolated as a microbial metabolite. Mutual p r o d r u g forms (esters) of t h e olivanic acids MM22382 and MM13902 with a renal dehydropeptidase I inhibitor w e r e reported.loO Though urinary recoveries of t h e s e derivatives in t h e mouse w e r e about s i x t i m e s higher than those of t h e f r e e acids, recoveries still w e r e low (1.8% and 8%). T h e k v i t r o activity and 8-lactamase stability of t h e carbapenem RS-533 was d e s c r i b e d v Neu has reviewed t h e special properties of imipenem t h a t contribute to i t s potent bioactivity, e.g. lack of a permeability barrier, high affinity for key PBPs and resistance to degradation by B-lactamases.lO2 Total s ntheses were ublished f o r 1a and IB-methylthienamycin,103 thienamycin,154 (+) - PS-5lt5 and t h e carpetimycins. 106

-

"jf&., 0

COOH

R , = ti R, -CH,OCH,CH(OH) -SCH,CH,NH,

'6

RJ

-

R,

17

=cn3cti(oS03n)- R,

= -ti

R3= -SO,H

Monocyclic B-lactams - A new class of monocyclic 13-lactams containing a 3 a formamido group, exemplified b formacidin CCG), was isolated from a bacterium of t h e genus Flexibacter.10y,108 Like t h e i r cephalosporin relatives t h e chitinovorins, described in 1984, formacidin C was highly s t a b l e to Wactamase. However, 4, though potent, has a very narrow spectrum of activity, bein limited to Pseudomonas, Proteus and Alcali enes SAR studies w e r e published which led to t h e selection of carumonam AMA-1080, 5) as a candidate for extensive biologicall l 2 and subsequent clinical evaluation. The results of SAR studies on I +xysulfonic acid derivatives of t h e monobactams (monosulfactams) h a v e been reported.l13,114 The antibacterial activity of t h e s e derivatives is, in general, limited to gram-negative organisms. Interestingly, their oral absorption properties a p p e a r to b e structurally specific t o t h e C-4 dimethyl compounds suggesting t h a t absorption occurs by a facilitated transport system. 5430,213 (20) was selected for f u r t h e r biological evaluation. 115,1 16 A 1-sulfonylaminocarbonyl derivative, SQ83,360(Z), was selected f o r f u r t h e r study following t h e synthesis and testing of numerous analo s.I 17 This compound exhibited exceptional activity versus P. aeruginosa.1 I f 9 1 19 SAR studies also w e r e carried out on l d x y a c e t i c acid derivatives.1*0,121 Again, bioactivity was limited to gram-negative pathogens. Publications also appeared on t h e e f f e c t s of having heteroatom substitution at t h e B-position of t h e monocyclic ring,122 t h e discovery of t h e monobactams123 and a z t r e o n a m I 2 4 and on a naturally*ccurring chlorinated nocardicin.125,126

3-

&Lactam Antibiotics

Chap. 13

Dunn

135

Rl

- CH,OCONH,

-CH,COOH

- C H,C

21 -

- CH,

00H

-H

- C (CH,), COOH

- CH,

-H 0

-

B-Lactamase Inhibitors Further studies with t h e penicillanic acid sulfone derivative, YTR-830, demonstrated t h a t when combined with ampicillin i t is as e f f e c t i v e as clavulanic acid and m o r e e f f e c t i v e than sulbactam in inhibiting 8-lactamases, especially those of chromosomal origin.127 A review of t h e mechanism of action of B-lactamase inhibitors was published.128 T h r e e reports also appeared describing both mechanistic and biochemical aspects of 13-lactamase inhibition. 1 29-1 31 Biosynthetic Pathways and Enzymes - A number of publications appeared in 1985 which describe various aspects of t h e biosynthesis of 8-lactams. The stereochemistry of ce halosporin C biosynthesis s t a r t i n g from chiral methyl valine was reviewed.lf2 One study showed t h a t t h e &methyl of penicillin N labeled from t h e chiral methyl of valine suffered c o m p l e t e epimerization in t h e oxidative ring expansion to deacetoxycephalosporin C.133 The conversion of t h e l a t t e r to deacetylcephalosporin C in Acremonium s t r i c t u m was shown to proceed with retention of c ~ n f i g u r a t i o n . The ~ ~ ~incorporation into isopenicillin N of 13Cand 15N-labeled precursors using a cell-f r e e system from C, acremonium was studied.135 The enzymes deacetoxycephalosporin C synthetase and deacetoxycephalosporin C hydroxylase w e r e shown to b e distinct and separable enzymes in & clavuligerus but w e r e not separable in C, a ~ r e r n o n i u m . ~Two ~~ general reviews of 13-lactam biosynthesis w e r e published.15/,15s Biosynthetic studies also appeared on carbapenems,l39 thienamycinl4o,l4l and clavulanic acid.142~143 Using purified biosynthetic enzymes from C. acremonium and & clavuligerus s u l f u r c o n t a i n i n g s i d e c h a i n derivatives of penicillins and cephalosporins w e r e prepared and found to b e more a c t i v e t h a n their naturally-occurring ~ o u n t e r p a r t s . l ~ 4 - 1 ~Preliminary 6 amino acid sequencing has been carried out on t h e active s i t e of PBP It1147 and PBP 5148 from E. coli and on t h e terminal amino acids of isopenicillin N s y n t h e t a s e from a~remoniurn.~49 A c t i v e s i t e specific mutations in P B P 3 of E. cp Jl produced an enzyme with reduced affinity for cephalexin.150

--

136

Section I11

- Chemotherapeutic Agents

Sciavolino, Ed.

References

I. 2. 3. 4. 5. 6. 7. 8. 9.

10. 11. 12.

13. 14. 15.

16. 17. 18. 19. 20. 21. 22 23. 2 4. 2 5. 26. 27. 2a 29. 30. 31. 32. 33. 3 4. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 5 2.

53.

z,

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4,

2,

u,

z,

2%

Chap. 13 54.

5 5. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 7 3.

74. 75. 76. 77. 78. 79. 80.

81. 82

83. 84. 85. 86. 87. 88.

89. 90. 91. 92. 92 94. 95. 96. 97. 98. 99. 100. 101. 102. 103.

B-Lactarn A n t i b i o t i c s

Dunn

137

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c.

138 104. 105. 106. 107. 108. 109.

110. 111. 112. 1 1 3.

1 14.

I 15. 116. 117. 118.

119. 1-20.

121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132.

133. 134. 135.

136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150.

Section I11

- Chemotherapeutic Agents

Sciavolino, Ed.

T. lirnori and M. Shibasaki, Tetrahedron Lett., 26, 1523 (1985). H.H. Wasserman and W.T. Han, Tetrahedron Lett., 2,3747 (1984). M. Aratani, H. Hrai, K. Sawada, A. Yamada and M. Hashimoto, Tetrahedron Lett., 26, 223 ( I 985). N. Katayarna, Y. Nozaki, K. Okonogi, H. Ono, S. Harada and H. Ckazaki, J. Antibiot., 38, 1 1 17 (1 985). T. Hida, 5. Tsubotani, N. Katagarna, H. Okazaki and S. Harada, J. Antibiot., 2, I128 (1985). M. Sendai, S. Hashiguchi, ?A. Tornirnoto, S. Kishimoto, T. Matsuo, M. Kondo, M. Ochiai, 3. Antibiot., 2, 346 (1985). P. Angehrn, Chemotherapy, 2,440 (1985). A. Imada, M. Kondo, K. Okonogi, K. Yukishigi and M. Kuno, Antirnicrob. Agents Chemother., 27, 871 (1985). R.J. Fass and V.L. Helsel, Antimicrob. Agents Chernother., 834 (1985). W.H. Koster, W.A. Slusarchyk, T. Dejneka, D. Kronenthal, M.G. Perri, F.C. Pilkiewicz, F.L. Routh, J.E. Sundeen, E.R. Weaver and R. Zahler, 25th ICAAC, 368 (1985). C. Yoshida. T. Hori, K. Mornonoi, K. Nagurno, J. Nakano, T. Kitani, Y. Fukuoka and 1. Saikawa, J. Antibiot., 2, I536 (1985). S.K. Tanaka, K. Bush, D.P. Bonner, R. Schwind, L Lalarna, F. Liu, 8. Minassian, S.A. Smith and R.E. Sykes, 25th ICAAC, 369 (1985). J.M. Clark, S.J. Olsen, D.S. Weinberg, M. Dalvi, R.R. Whitney, D.P. Bonner and R.E. Sykes, 25th ICAAC, 370 (1985). H. Breuer, G.S. Bisacchi, J.M. Drossard, P. Ermann, W.H. Koster, D. Kronenthal, P. Kuester, K.R. Lindner, H. Straub, U.D. Treuner and R. Zahler, 25th ICAAC, 371 (1985). S.K. Tanaka, K. Bush, D.P. Bonner, R. Schwind, F. Liu, 6. Minassian, S.A. Smith, D. Visnic and R.E. Sykes, 25th ICAAC, 372 (1985). J.M. Clark, R.R. Whitney, S. 3. Olsen, D.S. Weinberg, M. Dalvi, D.P. Bonner and R.E. Sykes, 25th ICAAC, 373 (1985). H. Ereuer, H. Straub, U.D. Treuner, J.M. Drossard, H. Hoehn and K.R. Lindner, J. Antibiot., 38, 813 (1985). S.R. Woulfe and M.J. Miller, J. Med. Chern., 2, 1 4 4 7 (1985). N. Noguchi, H. Masuya, T. Sugawara, Y. Kawano, T. Matsuo and M. Ochiai, J. Antibiot., 2, 1387 (1985). R.E. Sykes and D.P. Bonner, Rev. Infect. Dis., 7 (Suppl. 4), S579 (1985). R.E. Sykes and D.P. Bonner, Am. J. Med., r(1985). LJ. Nisbet, R.J. Mehta, Y. oh, CH. Pan, C G . Phelen, M.J. Polansky, M.C Shearer, A.J. Giovenella and SF. Grappel, J. Antibiot., 2, 133 (1985). J.A. Chan, E.A. Shultis, J.J. Dingerdissen, C W . DeErcase, C.D. Roberts and K.M. Snader, J. Antibiot., 38, 139 (1985). N.X. Chin and H.C. Neu, 25th ICAAC, 382 (1985). J.R. Knowles, ACC. Chern. Res., IS, 97 (1985). W.S. Faraci and R.F. Pratt, Biochemistry, 2,903 (1985). C.L Dmitrienko, C.R. Copeland, L Arnold, M.E. Savard, A.J. Clarke and T. Viswanatha, 34 (1985). Bioorg. Chem., M. Cole in "Antirnicrob. Agric. Proc. Int. Symp. Antibiot. Agric.: Benefits Malefits," 4th, M. Woodbine, ed., p.5, Butterworth, London (1984). CA. Townsend, J. Nat. Prod., 708 (1985). C.A. Townsend, A.B. Theis, AS. Neese, EB. Barrabee and D. Poland, J. Am. Chem. Soc., 107, 4760 (1 985). C.A. Townsend and E.B. Barrabee, 3. Chern. Soc., Chem. Comrnun., 1586 (1984). R.L Baxter, C.J. McCregor, C.A. Thornson and k L Scott, J. Chern. Soc., Perkin Trans. I , 369 (1985). S.E. Jensen, D.W.S. Westlake and S. Wolfe, J. Antibiot., 3, 263 (1985). D.E Cane, "Enzyme-level Studies of the Biosynthesis of Natural Products," in Enzyme Chern., C.J. Suckling, ed., Chapman & Hall, London, U.K., p. 196 (1984). J.F. Martin and P. Liras, Trends Eiotechnol., 2, 39 (1985). K. Kubo, T. Ishikura and Y. Fukagawa, J. Antibiot., 622 (1985). J.M. Williamson, R. Meyer and E. Inamine, Antimicrob. Agents Chemother., 2, 478 (1985). J.M. Williamson, E. Inamine, K.E. Wilson, k W . Douglas, J.M. Liesch and G. Albers-Schoenberg, J. Biol. Chem., 4637 (1985). C.A. Townsend and M.F. Ho, 3. Am. Chern. Soc., 107,1065 (1985). LA. Townsend and M.F. Ho, J. Am. Chern. Soc., 107,1066 (1985). S. Wolfe, C Lubbe, S.E. Jensen, H. Hernandez and A.L. Demain, J. Antibiot., 2, I550 (1985). S. Wolfe, LJ. Hollander and A.L Dernain, Bio/Technology, 635 (1984). C. Lubbe, S. Wolfe, J.E. Shields, S.W. Queener, N. Neuss and A.L. &main, J. Antibiot. 3, 1792 (1985). 3448 (1985). R.A. Nicholas, H. Surnuki and J.L. Strorninger, Biochemistry, R.A. Nicholas, F. Ishino, W. Park, M. Watsuhashi and 3.L. Strorninger. J. Eiol. Chem., 260, 6394 (1985). J.& Baldwin, J. Cagnon and H, Ting, FEBS Lett, 188,253 (1985). P.J. Hedge and B.G. Spratt, Eur. J. Biochern., 151,1 1 I (1985).

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Chapter 14. Quinolone Antibacterial Agents J a m e s B. C o r n e t t and M a r k P. Wentland S terling-W int hrop Research I n s t i t U t e Rensselaer, N Y 12144

Introduction*

-

The renewed i n t e r e s t i n quinolone antibacterials t h a t began 5 years a g o with t h e f i r s t descriptions of norfloxacin (NOR), pefloxacin (PEF), and enoxacin (ENO) has continued unabated. After two decades of only modest improvements in t h e antibacterial potency, t h e activity of t h e new fluoroquinolones f a r surpasses t h a t of t h e original quinolone, nalidixic acid (NAL, I). T h e most significant changes m a d e in t h e quinolone nucleus, addition of fluorine and piperazine, have provided t h e s e fluoroquinolones with a c t i v i t y a a i n s t Gramnegative b a c t e r i a t h a t rivals t h a t of t h e major classes of antibiotics.

'''

,,#

Previously relegated to t h e t r e a t m e n t of UTI, t h e increased potency of t h e new fluoroquinolones holds promise f o r a g r e a t l y expanded clinical use. This includes t h e potential f o r t r e a t m e n t of bacterial prostatitis, gastroenteritis, osteomyelitis, s o m e pneumonias and infections caused by multiply-resistant EnteroThe possibility f o r such b a c t e r i a c e a e and methicillin-resistant staphylococci. clinical use has motivated at l e a s t eleven major pharmaceutical firms to engage in t h e R&D of quinolone antibacterials. This has resulted in clinical trials with at least eight different fluoroquinolones throughout t h e world, of which four have received approval for clinical use outside t h e U S . The first of t h e s e new fluoroquinolones is e x p e c t e d t o r e a c h t h e U.S. m a r k e t in 1986.

'

Relative to t h e f i r s t commercially introduced fluoroquinolone, NOR, subsequent analo ues have shown g r e a t e r oral absorption (PEF, ENO), increased serum half-life (PEF!, overall increased potency in v i t r o (CIP) and an increased s e c t r u m to include Gram-positive cocci (CI-934) and anaerobic b a c t e r i a (DIF)." Along with t h e intense e f f o r t to design more potent derivatives, a major t h r u s t i n development has been to provide formulations a c c e p t a b l e f o r intravenous use. If successful, fluoroquinolones could provide both oral and parenteral t h e r a p y for a broad range of bacterial infections i n both hospitalized and outpatient populations.

'

The chronology of quinolone development i n chemistry and biology prior to This report will c o m l e m e n t recent 1985 was t h e subject of a previous review.' reviews describing t h e mechanism of action and r e ~ i s t a n c e , ~ " toxicity,' pharmacology' and SAR's"' of t h e quinolone antibacterials and f o c u s on t h e relevant l i t e r a t u r e of 1985. The biochemical t a r g e t of t h e quinolones is t h e bacterial DNA gyrase, an e x a m p l e of t h e t y p e I1 topoisomerase class of enzymes c

*Abbreviations used in this report: AMI-amifloxacin; CIP-ciprofloxacin; DIFdifloxacin; ENO-enoxacin; NAL-nalidixic acid; NOR-norfloxacin; OFL-ofloxacin; PEF-pefloxacin; UTI-urinary t r a c t infections. Copyright 0 1986 by Academic Press, Inc. ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21

All rights of reproduction in any form reserved.

140

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S c i a v o l i n o , Ed.

that a r e described in a s e p a r a t e report in this Volume.8a For those quinolones t h a t have been studied clinically, human pharmacokinetics and efficacy will b e stressed. Where t h e r e has been l i t t l e or no human d a t a reported? preclinical laboratory d a t a will be presented. Whereas NOR was t h e dominant quinolone during 1980-84, CIP became t h e in vitro class standard during 1985 with OFL rapidly emerging as t h e m a r k e t standard.

C i r o f l o d n (2) is t h e most potent of t h e quinolone antibacterials.' As with o t h e r quinolones, its in vitro a c t i v i t is not enhanced, nor antagonized by t h e presence of other antibacterial agents"' lY but it is reduced by divalent Mg." The pharmacokinetics of CIP have been determined following oral and intravenous administration of single or multiple doses.I2 Peak serum concentrations were proportional to t h e dose with values of 0.38 or 3.62 pg/ml achieved a f t e r single oral doses of 100 o r 1000 mg." No significant differences between HPLC and microbiological assay values were found in t h e serum of singly" or multiply15 dosed subjects. Significant differences were noted, however, by t h e t w o methods in two other The level of CIP metabolites in urine, as percent of total drug in urine, was g r e a t e r for a 50 m dose administered orally (42.7%) relative to t h e s a m e dose given i v (29.7%hF6 These d a t a suggest a first pass metabolism e f f e c t of CIP' leading to biologically a c t i v e metabolites in t h e bile'' and in t h e ~ r i n e . ~ ~ ' ~ ' ' ' ~ ' ~ ~

M o s t studies show similar pharmacokinetic profiles for CIP with oral and iv d o ~ i n g . ~ ~ " ' ' ~ ~When ' ~ ~ compared ,~~ in t h e s a m e study, CIP showed approximately 60 t o 77% bioavailability by t h e oral r ~ u t e . ' ~ ' " CIP is widely distributed giving volumes of distribution values ranging from 2.0 to 2.7 l/kg a f t e r iv doses of 50 to 200 mg.16'18'20 Since normal body water is 0.6 I/kg, this indicates distribution into secondary tissue compartments. CIP is reportedly taken up into human neutro hils where it e x e r t s a bactericidal e f f e c t against intracellular staphylococci. P 1 CIP has been used clinically to t r e a t a variety of bacterial infections includin bacteremia,2' deep soft tissue infection^'^-^' and abscesses, GI,22y2a26 UTI, '-2 ' ' 2 7 ' 2 8 and pulmonary''-2 'inf ections, chronic otitis,' osteom y e l i t i ~ , ? ~ - ~gonorrhea2' ' and GI decontamination.26 Instances have been reported of CIP-resistant bacteria from patients receiving oral or iv the rap^^"^' and one report of h e m a t ~ r i ahas ~ ~appeared. In one study side e f f e c t s were noted in 12 of 42 patients with liver enzyme elevations being t h e most frequent ( 5 patients). 2 3

''

Norfloxacin (3) was t h e f i r s t of the 6-fluoro-7-piperazinylquinolonesto reach t h e market (1983) and should be available for clinical use in t h e U.S. in 1986. An excellent review of t h e antibacterial, pharmacokinetic and therapeutic properties of NOR was recently published." The in vitro potency of NOR is less than t h a t of CIP or OFL and t h e oral absorption is less than t h a t of OFL or EN0.3 Nonetheless, NOR is a c t i v e against those bacterial pathogens responsible for infections of t h e eye,34 the urinary gastroenteritis 37'38 and some genital pathogens,39 while less active against anaerobic bacteria' and some selected bacteria such as Pseudomonas maltophilia and S. faecalis.'

'

The normally prescribed dosage of NOR (400 mg, PO) provides serum levels near 1.5 pg/ml. With 30% of the dose e x c r e t e d i n t o t h e urine (peak concentrations of 180 to 480 ~ # / m l ) , NOR ~ ~ has proven to be effective therapy f o r both uncornplic a t e d and a c u t e urinary t r a c t i n f e c t i o n ~ . ~ " ~ ~ - "There is little excretion of NOR i n t o the bile, but NOR has been measured in several other tissues and body fluids,39 including human prostatic t i ~ s u e ' and ~ prostatitis has been effectively t r e a t e d with NOR.46 The drug reduces t h e Enterobacteriaceae in t h e anal and vaginal flora." NOR may thus be e f f e c t i v e in prophylaxis against bacterial sepsis

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in neutropenic patients.33 Other t h e r a p e u t i c uses for NOR may include e a r , nose and t h r o a t infections and s o m e infections of t h e respiratory t r a c t other than those cause by neumoncocci. Clinical trials for t h e s e indications have been conducted in Japan. ?p3

--

Ofloxacin (4) potency is close to t h a t of CIPc’3”39~c’’48 and greater than CIP f o r some bacteria. 3 9 ’ 4 7

This tricyclic quinolone has shown excellent potency in v i t r o against e n t e r o p a t h o g e n ~a, ~ mycobacteria, anaerobes” and genital pathogens. The drug appears to p e n e t r a t e cellular membranes and inhibits bacterial growth within host tissue^.^^'^^ The protective action of OFL in experimental infections indicates t h a t t h e drug is well absorbed and this observation has carried over into clinical studies.’ 0’52

’’

4,

OFL has been compared with trimethoprim/sulfa, nitrofurantoin, doxycycline and cefuroxime in clinical t r i a l s i n Europe and Japan. Single dose (100 mg, PO) therapy has been successful for UTI” while Ion e r t r e a t m e n t t i m e s (7-10 days) and higher doses have been used m o r e f r e q ~ e n t l y . ~ ‘ More a t t e n t i o n has been focused recently on respiratory infections54 where 200 mg BID has proven m o r e e f f e c t i v e than d o ~ y c y c l i n eor ~ ~cefuroxime.’ 3 ’ 5 5 Other bacterial infections successfully t r e a t e d have included b i l i a r ~ , ~pyelonephritis, prostatis, osteoarthritis, t r a u m a t i c and post-operative wound infections. Gynecologic infections have responded to OFL with c u r e r a t e s (95%) equal to minocycline against ChlamvdiaS5 and long t e r m t r e a t m e n t (6-8 months) has been successful f o r t r e a t i n g otherwise resistant cases of t u b e r c u l o s i ~ . ~Pharmacokinetic ~ measurements of OFL in lung” and prost a t i c ” tissues, as well as bile,5 are consistent with observed clinical efficacy. The f e w side effects reported” include nervousness, GI upset and pain, skin reaction and transiently e l e v a t e d liver transaminases without a n y signs of renal toxicity.60 OFL levels i n serum (ca. 4 &ml) and blister fluid (ca. 2 pg/ml) have been measured followin oral dosing while bile contained 26% of t h e OFL as glucuronide The rate of oral drug absorption and t h e serum half-life (9.0 hr) was reduced by foods9 while in uremic patients t h e plasma half-life increased f r o m 4.4 hr to 13.2 hr with a reduction in urine recovery from 74% to 20% relative to patients with normal glomerular f i l t r a t i ~ n . One ~ ~ crossover comparative pharmacokinetic study showed o r a l OFL to have 2-fold greater serum levels and urine recovery relative to t h e s a m e oral dosage (200 rng) of CIP.61 The synthesis and antibacterial activities of both OFL enantiomers have been reported.62 The levorotatory isomer was 8- to 128-fold m o r e a c t i v e in v i t r o than t h e dextrorotatory isomer against a variety of Gram-negative and Cram-positive bacteria.

’

conjugate^.^'

Enoxacin(5) is generally less potent than CIP o r OFL and particularly so with respect to s t r e p t o c ~ c c i . ~ ’ ~ However, ~’~~ E N 0 is more potent in vitro against Cram-negative b a c t e r i a including Pseudomonas than a z t r e o n a m o r t h e amino lycosides.”’ EN0 is well absorbed orally 6 9 6 B reaching s t e a d y state serum concentrations (peak and trough values of 3.5 and 1.3 &ml, respectively) by t h e third day of dosing (400 mg, BID, 7 days).68 I Serum half-life values range f r o m 4.4 to 6.7 hr67’68 with 40% t o 70% of t h e dose appearing in t h e urine6‘ as E N 0 and 4 a c t i v e metabolites.6E One report described single intravenous doses (10 to 800 mg) to human volunteers as being well t o l e r a t e d and providing slightly higher plasma levels (5.8 &mI) than t h e s a m e oral dose of 800 mg (4.0 ~ g / m l ) . ~E’ N 0 is capable of penetrating human leukocytes and equally potent as rif ampin in killing ingested

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b a ~ t e r i a . ~ ' The capability of tissue penetration is also seen i n pharmacokinetic studies where levels of E N 0 in human sputum, prostatic tissue and bile exceeded serum or plasma level^.^' E N 0 was also found in human tears, saliva, blister fluid and middle ear exudates.68 Similar results have been found for E N 0 penetration of prostatic tissue and the CSF of This ability to cross the blood-brain barrier may contribute t o t h e CNS-related side effects observed in clinical trial^.^''^' 7 4 Clinical trials to d a t e have relied upon oral E N 0 therapy (general1 200 to 400 mg/day, BID) to treat infections of the r e ~ p i r a t o r y , ~ ~u "r i~n a r ~ k 7Y~ ' ~ GI and biliary tracts,6 skin and soft tissue," as well as gynecological and ophthalmological infections.68 The majority of these trials with respiratory or urinary tract infections have shown E N 0 therapy to be 70 to 80% effective6' and in the case of acute gonorrhea, 100% effective.76 Side effects in humans were reportedly dose related6' increasing from 0.9% with 200 mg/day t o 13.3% with 900 mg/day oral doses and may have been related to an interference with theophylline metabolism in some

Pefloxacin (6) and NOR were the first of several 6-fluoro-7-piperazinylquinolones

to be described. PEF has & & activity similar t o NOR and E N 0 against Enterobacteriaceae and P. aeru inosa but is 4- t o 8-fold more potent against 2. aureus. 7 7 CIP is cons&r*e potent than PEF against Gram-negative organisms but they generally show similar activity against Gram-positive cocci. In experimentally induced Pseudomonas pneumonia in guinea pigs, PEF and CIP at the same dose (im) were highly efficacious in increasing survival times and decreasing bacterial counts in the lungs of surviving animals." Against an experimental infection model with methicillin-resistant 5. aureus, PEF at 30 mg/kg, (im) was as efficacious as vancomycin (25 mg/kg, iv) while cephalothin was i n e f f e ~ t i v e . ~ '

-

At a dose of In humans, PEF exhibited a relatively long serum half-life.' 400 mg (PO or iv), a serum half-life of 11 hr was observed." Areas under t h e plasma concentration curves were essentially identical indicating complete oral bioavailability. A t this same dose, peak serum levels of PEF were 3.8 and 4.2 kg/ml for PO and iv administration, respectively.' Urinary recoveries of PEF were 11% of a 400 mg oral dose providing concentrations well in excess of t h e MIC's against most uropathogens.*' PEF is extensively metabolized with NOR being the major metabolite.' Biliary excretion of PEF, either as intact drug or metabolites, can account for 20-30% of an oral dose and its pharmacokinetics were studied in patients with cirrhosis of the liver." Following a single dose of PEF ( 8 mg/kg, iv) t h e mean serum half-life, although highly variable, was significantly longer (35 hr) in cirrhotic patients than in normal subjects."

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Amiflcucacin (7) is t h e only 6-fluoro-7-piperazinylquinolone reported t h a t does not have a carbon directly a t t a c h e d to t h e I-position; i t has instead a methylamino appendage.82 AM1 has broad in v i t r o a c t i v i t y comparable to NOR, PEF and E N 0 other quinolones AM1 has relatively low but is less active than CIP.4’BZ’BJLike activity against most anaerobes. I t w a s more e f f e c t i v e i n vitro t h a n a z t r e o n a m in inhibiting amikacin-resistant E. aeruRinosa.84 Against Gram-negative clinical isolates from cancer patients, AMI, HR 810, and imipenem exhibited potent in vitro activitv which was considerably Rreater t h a n t h a t exhibited by ceftazidime.m AM1 and CIP had similar in vitro activity against 29 Leaionella Golates but both w e r e much less potent t h a n rifarnpin.O6 Pharmacokinetic studies with r a t s indicated t h a t AMI, as with man quinolones, was well absorbed orally and rapidly e x c r e t e d i n t o t h e urine. 8 2 9 x 7 The elimination half-life of AM1 was 2.2 hr in rhesus monkeys given 10 m d k g (base equivalents) of AM1 mesylate intravenously.*’ Concentrations of AM1 in p r o s t a t i c secretion and p r o s t a t i c interstial fluid of dogs medicated with AM1 (iv) exceeded t h e MIC’s of most pathogens involved in chronic bacterial prostatitis.”

Diflowcin (A-56619, 8) and A-56620 (9) are I-(4-fluorophenyl)-substituted quinolones which exhibit excellent & vitro and in vivo activity against a wide variety of and E. cloacae, A-56620 organisms, including anaerobes.Against E. showed comparable in vitro activity to CIP (MIC90 < 0.06 FgTml) but was generally less a c t i v e t h a n CIP against o t h e r Gram- negative^.'^ A-56620 was less active t h a n CIP but two to eight times more a c t i v e t h a n NOR against Gram-positive isolates. Against Chlamydia trachomatis DIF exhibited similar v i t r o a c t i v i t y as tetracycline while A-56620 and OFL w e r e somewhat less p o t e n F DIF, A-56620, and CIP had similar i n vitro activity a g a i n s t Bacteroides (including B. f r a ilis), Clastridium and other anaerobe spp. while NOR was considerably less active, --%t-.6 although clindamycin was more potent than any quinolone tested.96 In r a t s and dogs DIF showed essentially complete o r a l bioavailability resulting in hi h peak serum levels and extended serum half lives relative t o other quinolones. 9 O,’? In addition to 1-piperazinyl and 4-methyl-1-piperazinyl at position-7, t h e 3amino-I-pyrrolidi;yl group was also shown to i m p a r t good activity to t h e s e a r y l fluoroquinolones. The in vitro activity of one such analogue, A 4 0 9 6 9 (10) was 2to 16-fold more potent t h a n CIP against Gram-positive organisms and approximately 10-fold m o r e potent than CIP against B. fraailis. Against P. a e r u inosa and e n t e r i c bacteria, A 4 0 9 6 9 was approx. 4-fold less potent than CIP? Qualitatively similar comparative d a t a were noted in mouse protection tests against Grampositive and Gram-negative organisms.”

+

Both enantiomers of an aryl fluoroquinolone have been prepared.’ O 0 They differ from DIF only at t h e 7-position; instead of a piperazine moiety t h e s e new agents have a 2-hydroxymethyl- I-pyrrolidinyl substitution. The (Rhenantiomer had approximately 60- and 30-fold g r e a t e r i n vitro activity against and S. a u r e u s respectively, than t h e (Sbenantiomer. Pirfloxacin, I-ethyl-6-fluoro-1,4dihydro-4-oxo-7-(1H-pyrroI-I-yl~-3-quinolinecarboxylicacid, has been synthesized and has i n vitro activity reported to be similar to ENO.’O 1

-

s.

CI-934 (11) has broad in vitro activity and is particularly e f f e c t i v e against Crampositive bacteria.lo2 For example, CI-934 is 4-fold m o r e potent in v i t r o t h a n OFL against staphylococci. Against Pseudomonas spp., CI-934 has much higher MIC’s than against t h e Enterobacteriaceae. The in vitro a c t i v i t y of CI-934 against E.

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franilis was comparable to CIP but 2-fold and 8-fold less potent than clindamycin and metronidazole, respectively.' CI-934 was 4-fold more potent than CIP and OFL against Clostridium difficile.lO' Oral efficacy of (21-934 has been demonstrated in mice experimentally infected with g. coli, 5. aureus, and 5. o enes Upon oral administration of the *(25 mg/kg) to dogs a peak plasma level of 5.8 &ml occurred at 3 hr with an apparent half-life of 8.4 hr.lo6 CI-934 had an oral bioavailability of 57% in dogs.

S-25930 (12) and S-25932 (13) a r e two new analogues of flumequine (14)"' in which the hydrogen at position-8 has been replaced by methyl and I-imidazolyl,

respectively. Against a variety of Gram-negative and Gram-positive organisms, including anaerobes, S-25930 and S-25932 were 2- to 4-fold less potent in vitro than CIP and had activity similar t o E N 0 and OFL. l o * In another in vitro study S-25930 and S-25932 displayed activity similar to CIP against streptococci, Neisseria spp., H. influenzae Bacteroides spp., Clostridium spp., and anaerobic Gram-positive cocc-ainst the Enterobacteriaceae and p. aeruninosa the two quinolones were 20-fold and 60-fold less active than CIP, respectively. S-25930 was approximately 2-fold more active h vitro than S-25932. S-25930 showed excellent a c t m y , while S-25932 exhibited poor in vitro activity, against an isolate of E. onorrhoeae resistant to rosoxacin but sensitive to NAL. Based on this and studies with other l.gonorrhoeae isolates, quinolone resistant Neisseria were divided into two groups. One t h a t was susceptible t o quinolones having heterocyclic (e.g. I-piperazinyl, bpyridinyl, or I-imidazolyl) substitution; the other susceptible t o quinolones 12, RmCH3 having methyl or hydrogen substitwnts (e.g. SmN 25930, NAL, or flumequine). In vivo compari13, son of S-25930 and NOR in mouse protection E, R-H tests (PO) showed a similar potency/s ctrum profile as the in vitro experiments.ll'ln the adult rat, S-25930 was consistently detected in brain tissue while NOR was not.' * Comparison of t h e in vitro properties of both optical isomers of 5-25930 indicated the (9-enantiomer to be more potent than the (Rbisomer.'

+

-

A series of novel mono- (15) and tricyclic (16) analogues of the quinolones has been r e ~ 0 r t e d . l ' ~ Ro 13-5478 (15; X=4-NMe was the most potent member of that subserieg having in vitro activity against E. @ and 2. aureus comparable to NAL. Because several of the monocyclic compounds showed CNS stimulation, an attempt was made to reduce t h e CNS activity by restricting t h e conformation of the phenyl ring with respect t o t h e 4-pyridone ring. To that end a sterically encumbered variant I5 (X,R =2,6-diMe-4X N M e was made in which t h e ri&s a r e nearly 2 perpendicular. This analogue lacked CNS stimulation, however, i t was devoid of antiR = C H 2 C H 3 , R1.H bacterial activity. Several examples of tricyc12, R1 (R * CH2CHCH3

-

s,

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l i c derivatives 16, i n which t h e rings are planar, w e r e found to have i n v i t r o and 5. aureus. T h e most a c t i v e tricyclic w a s Ro 14-9578 activity against E. (16; X=3',4'aCH CH 0-1 and had antibacterial potency g r e a t e r than NAL. In was c o n t r a s t to t h e c&ralAy studies of S-259301 " t h e (Rbenantiomer of 16 (X=H) considerably m o r e p o t e n t in vitro t h a n t h e (Shisomer. R o 13-5478 and Ro 14-9578 had similar in vitro DNA gyrase (g. & inhibitory activity t h a t was somewhat g r e a t e r t h a n NAL. Both compounds had substantially reduced a c t i v i t y against a NAL resistant g. These d a t a indicate t h a t t h e s e mono- and tricyclic analogues act like t h e quinolones by inhibiting t h e A subunit of bacterial DNA gyrase.

a.

A new series of l-cyclopropyl-1,8-naphthyridines containing a 4-substituted-3aminomethyl-I-pyrrolidinyl appendage at t h e 7-position has been reported. l 1 One of t h e most potent analogs, AT-3765 ( I f ) , had in vitro and i n vivo (mouse, iv) Grampositive activity equal to o r up t o 10-fold g r e a t e r t h a n ? T l 6 In similar tests against g. & and 11. aeruninosa, however, CIP was 2-fold more a c t i v e t h a n AT3765. The --isomer of AT-3765 showed comparable in vitro activity as did t h e fluoro (cisand trans) and deschloro analogues. A related quinolone, AT-3295 (18, was shown to have similar i n v i t r o a c t i v i t y to CIP a ainst Gram-negative bacilli (including p. aeruRinosa) and anaerobic bacteria. However against Grampositive cocci, AT-3295 was %fold more potent t h a n CIP. Upon comparison of AT3295 and CIP in mouse protection models (PO and iv), a similar profile to t h e h vitro study emerged."' The t w o diasteriomers of AT-3295 showed comparable vitro activity.

"

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AM-833 (19), although somewhat less a c t i v e than CIP in vitro, was 2- to 8fold more a c t i v e t h a n CIP when administered orally t o m i c e infected with 2. aureus, P. a e r u inosa 5. pneumoniae, o r 2. marcescens. l 9 Following a single o r a l dose of 10-AM-833 o r CIP to mice, mean peak serum levels w e r e 2.4 to 0.4 pg/ml, respectively."' Lung a n d kidney levels of AM-833 w e r e much higher t h a n t h o s e of CIP.

'

Another 6,8-difluoroquinolone, NY-198 (20), has a 3-methyl-1-piperazinyl appendage at position-7 instead of t h e more common 4-H- o r 4-methyl-lpiperazinyl moiety.'*l It has broad in vitro activity comparable to NOR and OFL and is up to &fold m o r e potent in vivo. Following a 20 mg/kg oral dose of [ 14C] NY-198 to dogs, a C m a x of 11.1 pg/ml ( t o t a l radioactivity) was observed within 1 hr with a serum half-life of 6.9 hr. NY-198 showed complete oral absorption in dogs with 61% of dose e x c r e t e d into t h e 0-48 hr urine.'22

a

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REFERENCES

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1. D.C.HooDer and J.S. Wolfson. Antimicrob. AF. Chemother.. * 28.d 716 (1985). 2. R.J. Fa&, Ann. Int. sled., 400 (1985). 3. M.P. \\'entland and J.B. C o r n e t t , Ann. Rep. Med. Chem., 3 145 (1985). 4. D. Felrningham. M.D. O'Hare. V.J. Robbins. R.A. IVall. A.11. Williams. A.W. Crerner, G.L. Ridgway, a n d R:N. Gruneberg, Drugs Exptl. Clin. Res., 3 3 1 6 (1985). 5 . J.S. Wolfson and D.C. Hooper, Antimicrob. Ag. Chemother., 3 5 8 1 (1985). 6. J.T. Smith, Pharm. J., 299 (1984). 7. J.J. Schentag and J.hl. Domagala, Res. Clin. Forums, 3 9 (1985). 8. J. Domagala, L. Hanna, C. Heifetz, M. Hutt, T. hlich, J. Sanchez and h'l. Solomon, J. hled. Chem.

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3 394 (1986).

8a. L.F.Liu, Ann. Rep. Med. Chem., 2L, (1985). 9. I. Haller, Antimicrob. Ag. Chemother., 5 663 (1985). 10. S. How. D. Hobson. C. Hart and R. Webster. J. Antimicrob. Chemother.. 15. 5 3 3 (1985). 11. G. Hofiken, K. Boiner, P.Glatze1, P. Koeppe a n d H, Lode, Eur. J. Clin. nlFrob., 3 345 (1985). 12. B. Ledergerber, J.-D. Bettex, B J o o s , M. Flepp and R. Luthy, Antimicrob. Ag. Chemother., 350 (1985).

3

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363 (1984). 13. D. Hoffler, A. Dalhoff, W. Gau, D. Beermann and A. Michl, Eur. J. Clin. Microbiol., 14. J.-M.Brogard, F. Jehl, H. Monteil, 37. Adloff, J.-F. Blickle and P. Levy, Antirnicrob. Ag. Chemother., 28, 3 1 1 (1985). 15. 8. Joos, B. Ledergerber, ?J, Flepp, J.-D. Bettex, R. Luthy and W. Siegenthaler, Antimicrob. Ag. Chemother., 3 353 (1985). 1 6 . G. Hoffken, H. Lode, C. Prinzing, K. Borner and P. Koeppe, Antimicrob. Ag. Chemother., 3 375 (1985). 17. W. Wingender, K.-H. Graefe, W. Gau, D. Forster, D. Beermann and P. Schact, Eur. J. Clin. 355 (1984). Microbiol., 18. 1M. Gonzalez, A. Moranchel, S. Duran, A. Pichardo, J. Magana, B. Painter, A. Forrest and G. Drusano, Antimicrob. Ag. Chernother., 5 235 (1985). 19. G. Aronoff, C. Kenner, R. Sloan and S. P o t t r a t z , Clin. Pharmacol. Ther., 9 3 8 4 (1984). 20. G. Hoffken, H. Lode, C. Prinzing, K. Borner and P. Koeppe, Klin. Wochenschr, 9 Suppl. 4, 165 (1985). 21. C. Easmon and J. Crane, J. Antimicrob. Chemother., % 67 (1985). 128 (1985). 22. C. Ramirez, J. Bran, C. Mejia and J. Garcia, Antimicrob. Ag. Chemother., 23. H. Giamarellou, E. Daphnis, C. Dendrinos and G. Daikos, Drugs Exptl. Clin. Res., 11 3 5 1 (1985). 24. L. Eron, L. Harvey, D. Hixon and D. Poretz, Antimicrob. Ag. Chemother., 21, 3 0 8 3 9 8 5 ) . 5 6 3 A (1985). 25. C. Ericsson, P. Johnson, H. DuPont, J. Bitsura and F. d e la Cabada, Clin. Res., 26. M. Rozenberg-Arska, A. Dekker and J. Verhoef, J. Infec. Dis., 152, 104 (1985). 21. J. Boerema, B. Boll, H. Muytjens and J. Branolte, J. Antimicrob. Chemother., 3 2 1 1 (1985). 28. H. Giamarellou, A. Efstratiou, J. Tsagarakis, G. Petrikkos and G. Daikos, Arzneirn.-Forsch., 3 1775 (1884). 29. P. Loo, G. Ridgway and J. Oriel, Genitourin. Med., 6 1 3 0 2 (1985). 30. S. Chapman, D. Speller a n d D. Reeves, Lancet, 3 3 d 1 9 8 5 ) . 31. H. Humphreys and E. Mulvihill, Lancet, 3 3 8 3 (1985). 177 (1985). 32. F. Garlando, M. Tauber, B. Joos, 0. Oelz and R. Luthy, Infection, g, 33. B. Holmes, R. Brogden and D. Richards, Drugs, g,482 (1985). 34. D. Shungu, V. Tutlane, E. Weinberg and H. Gadebusch, Chernother., 3 112 (1985). 35. L. Verbist, Acta Clin. Belg., 40 167 (1985). 1 6 9 (1985). 36. P. Turgeon, J. Dubois and S. d f f e l , Curr. Ther. Res., 31. J. Morris, J. Tenny and G. Drusano, Antimicrob. Ag. Chemother., 3 442 (1985). 38. H. Goossens, P. deMol, H. Coignau, J. Levy, 0. Grados, G. Ghysels, H. Innocent and J-P, Butzler, Antimicrob. Ag. Chemother., 3 388 (1985). 39. J. Aznar, M. Caballero, M. Lozano, C. d e Miguel, J. Palomares and E. Perea, Antimicrob. Ag. Chemother., 5 76 (1985). 40. A. Chow, N. Cheng and K. Bartlett, Antimicrob. Ag. Chemother., 28 8 4 2 (1985). 41. D. Grimard and M. Bergeron, J. Antlmicrob. Chemother., 5 132 685). 4 2 2 (1985). 42. E. Goldstein, M. Alpert a n d B. Ginsberg, Antimicrob. Ag. Chemother., 43. J. Sabbaj, V. Hoagland and W. Shih, Antimicrob. Ag. Chemother., 3 297 (1985). 44. A. Schaeffer and G. Sisney, J. UroL, 1 3 3 , 6 2 8 (1985). 45. M. Bergeron, M. Thabet, R. Roy, C. Lessard and P. Foucault, Antimicrob. Ag. Chernother., 3 349 (1985). 46. M. Bologna, L. Vaggi, D. Flammini, D. Carlucci and C. Forchetti, Drugs ExptL Clin. Res., 3 95 (1985). 47 * C. Heppleston, S. Richmond and J. Bailey, J. Antimicrob. Chemother., 3 645 (1985). 48. P. ValeroCuillen, F. %Tartin-Leungo and I. Quintanilla, J. Antimicrob. Chemother., E, 254 (1985). 49. L. Dubreuil, J. Devos, C. Romond and A. Bryskier, PathoL BioL (Paris), g,4 2 1 (1985). 50. T. Kumada and H. Neu, J. Antimicrob. Chemother., 3 563 (1985). 51. A. Saito, K. Sawatari, Y. Fukuda, M. Nagasawa, 11. Koga, A. Tomonaga, H. Nakazato, K. Fujita,

i,

3

Y. Shigeno, Y . Suzuyama, I1,11 >1,9." PGF2a 1,15-lactone was effective in terminating early pregnancy in monkeys under circumstances where PGF& was ineffective. Table 1 - Prostaglandins

17 -

Chap. 17

Chemical C o n t r o l of F e r t i l i t y Bell, Batzold, Winneker

173

The most widely used method of pregnancy termination during the first 8 weeks of gestation is vacuum aspiration. The use of PGs for termination of t h i s stage of gregnancy is still in the exploratory stage but results are considered promising. Intravaginal administration of 24 or 25 or i m administration of 26 within 3 weeks after the first missed menstrual period were as effective as vacuum aspiration. Side effects included vomiting, diarrhea, and uterine pain but were of lower incidence than observed with the natural PGs. Late first trimester and early second trimester terminations by surgical means were associated with an increased incidence of complications such as cervical injury and hemorrhage. Preoperative cervical dilation by the PG analogues 2 2 , s and 25 by non-invasive routes and at sub-abortifacient concentrations resulted in a lower incidence of c~mplications.’~ Medically as opposed to surgically induced termination was the most common method used to terminate mid- to late second trimester pregnancy in four western countries. The technique consists of a two-stage administration of intra-amniotic hypertonic saline and extra- or intra-amniotic PGE2 or PGF Compound 22 is long-acting and thus suitable for single injection but is associat3 with a high incidence of gastrointestinal side effects; 2 was as effective as 22 and caused fewer gastrointestinal side effects. Intravaginal administration of 24 was as effective as 22 and caused no more gastrointestinal side effects than S, The best procedure may be pretreatment with one laminaria tent (for cervical dilation) for 12 h followed by im g.55 Male Contraception - Numerous classes of compounds have been identified as potential contraceptive agents for the male yet none has been accepted for human US^.^^''^ Spermatogenesis requires normal levels of the gonadotropins, LH and follicle stimulating hormone (FSH). Inhibins are peptides o_f gonadal origin that selectively inhibit FSH production both in vitro and in viva.'* 6 o Molecular weight estimates of these peptides vary from 3000-30,000 Daltons depending on the source and method of is~lation.’~ Inhibin-like peptides isolated from human seminal plasma have been characterized and the smallest, f3-inhibin-31, has been synthesized.’ -6

’

Several compounds have direct antispermatogenic activity but toxicity and unacce table side effects have prevented their development as male antifertility agentse6 Gossypol(27) was most effective in hamsters, followed by rats, monkeys and dogs and was relatively ineffective in rabbits and mice.61’62 Reversible antifertility effects have been produced in rats at doses of 7.5-30 mg/kg/day PO for 6-12 weeks with no significant toxic effects. In man, administration of 21 at a dose of 20 mg/day for 75 days followed by a maintenance dose of 50 mg/week caused sperm counts to fall below 4 million/ml after 3 Ho u months in 99% of subjects. Only 75% of men experienced a return to retreatment levels upon [w*] -22 7 2 cessation of treatment.‘ Compound 27 acts at multiple testicular sites (late spermatids, pachytene spermatocytes, Sertoli cells) to uncouple spermatozoa1 oxidative phosphorylation and t d inhibit lactic dehydrogenase-X activity.61 The problems of hypokalemia and irreversible sterility may prevent wide acceptance of gossypol.63 The racemate of 27 often is isolated from the cotton plant as a 1:l complex with acetic acid. The antifertility effects of gossypol reside in the ( - ) - e n a n t i ~ m e r . ~In ~ ’a~ study ~ of 18 gossypol derivatives substituted with various groups at the hydroxyl and/or aldehyde functions, only one showed modest activity.6 L

Sulfasalazine (281, a sulfonamide drug used for the treatment of ulcerative colitis, caused reversible infertility in many patients.669b7 In rats, at 600 mg/kg PO for 5 weeks, 3 decreased fertility to 27% of controls. In man, 2-4 g/day for 2

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months produced changes in sperm density and motility in ?zH approximately 60% of subjects without affecting serum gonadotropin or testosterone levels.6e In rat and man, 28 is metabolized to sulfapyridine .. and 5-aminosalicylic acid. Sulfapyridine treatment of male 28 rats (321 mg/kg/day x 8 weeks) resulted in significant decreases in the number of fetuses/pregnancy although the pregnancy rate was not affected.

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Phenoxybenzamine, an adrenergic blocking agent, inhibited ejaculation in some atients and was evaluated in rats and humans as a potential contraceptive Parenteral treatment of male rats with phenoxybenzamine (0.7 mg/kg/ 5 weeks) produced infertility in 6 of 7 rats which was apparently due to a paralysis of the muscles associated with the sex accessory glands leading to the absence of eja~ulation.~ In~studies of men experiencing premature ejaculation, 10-12 mg/day produced azoospermia following orgasm after 2-3 days of treatment and was reversible. Treatment for a t least one month did not affect serum gonadotropin and testosterone levels or blood p r e ~ s u r e . ~ Miscellaneous - The 1,2,4-triazole 29 (DL-111-IT) terminated pregnancy at low parenteral ED doses of 0.4-0.7 mg/ kg 5for 2 to 5 days in the rat, mouse, hamster and dog and was also active in baboon^.^' y 7 2 The compound, 29 which has no hormonal or antiMe0 hormonal activity, is believed to act as2 the uteroplacental complex, and has been selected for early pregnancy R H termination studies in women.73 Melatonin (30,R=H) is metabolized by oxidation a t -RH C-2 and C d . Chlorination of 30 30 to give 31 changed the c1 nplasma half-life in rats from 12-15 minutes to about 27 minutes. Compound 31 was more active than melatonin as an inhibitor of ovulation in the M. rat presumably because of 32 increased metabolic ~tability.~’ Melatonin and its 6-chloro derivative inhibited LH release R which accounted for the observed inhibition of ovul a t i ~ n . ~ The ’ synthetic conversion of the plant antifertility 33 product zoapatanol 32 to the R=(CH& C=CHCHZCOqH(CH2)3 bicyclics 33 resulted in compounds with greater contraCH3 gestational activity than 32 in R1=CH20H, CHO, COZH

gent!^'^'

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Chap. 17

Chemical Control of F e r t i l i t y Bell, Batzold, Winneker

the guinea pig, a result which suggested that the activity of 32 may be mediated by product(s) of in vivo oxidative c y ~ l i z a t i o n . ~ORG ~ 13811 (33, R'=COzH, R with CHOH instead of CO) caused interruption of pregnancy in mice, rats, guinea pigs, dogs, and baboons in single or multiple doses of 6 4 0 mg/kg/po depending on the species.76 Like PGF but less active, 33 is both uterotonic and vasoconstrictive, properties which cougcontribute to the interceptive activity. Bremazocine (34) and mop hine lowered serum LH levels and inhibited spontaneous ovulation in rats.7P Termination of pregnancy in mice by -35, a mechanism-based irreversible ("suicide") inhibitor of ornithine decarboxylase, resulted from inhibition of the marked activity of ornithine decarboxylase in the e m b r y ~ . ~ ' The compound also interrupts pregnancy in rats, rabbits, and hamsters and appears to be HO well t ~ l e r a t e d . ~ ' ' ~ '

-

34 cHF2

1

N"2

35 -

The successful termination of Summary early human pregnancy by t h e P receptor antagonist mifePriStOne could be regarded as the most significant development in female fertility control in the last few years. Although preliminary results suggest that this drug may lack sufficient efficacy to compete with existing methods when given alone, the validity of the approach has, nevertheless, been established. In a related and potentially equally important development, epostane, a P biosynthesis inhibitor, caused a fall in plasma P levels in early human pregnancy. Results of definitive pregnancy termination studies are not yet available.

PGs are now used for the termination of mid- to late second trimester pregnancy. Three synthetically modified PGs were clinically advantageous with respect to duration of action, side effects, and stability when compared with PGEz and PGFS Instrumental evacuation for pregnanc termination is increasing, a reflection of a shift from late to early abortion." The percentage of medical inductions among all abortions decreased in t h e W.S., Canada, and Sweden, again indicative of earlier abortions." The only accepted means of male contraception are surgical and barrier.'' Side effects and a significant incidence of irreversibility have impeded the development of gossypol; new derivatives with improved properties have not been reported. There have been no significant developments in the steroid hormone agonist field. R6FERENCB 1. 2. 3. 4. 5.

6. 7.

8.

168 (1979) M.R. Bell, R.G. Christiansen and H.P. Schane, Jr., Annu. Rep. Med. Chem. A S . Dutta and B.J.A. Furr, Annu. Rep. Med. Chem., 9203 (1985). M.J.K. Harper, Medicinal Research R e v i e w s 3 403 (1982). "Research on the Regulation o f Human Fertility", Vols 1 and 2, E. Diczfalusy and A. Diczfalusy, Ed., Scriptor, Copenhagen, 1983. "Abortion: Medical Progress and Social Implications", Ciba Foundation Symposium 115. R. Porter and M. O'Connor, Edn, Pitman, London, 1985. M.R.N. Prasad, J. B i o s c i . 5 Suppl. 2, 107 (1984). W.R. Jones in "Research on the Regulation o f Human Fertility", Vol. 2, E. Diczfalusy and A. Diczfalusy, Ed&, Scriptor, Copenhagen, 1983, pp. 810-832. G. Benagiano and F.M. Primiero, Drugs, 5 570 (1983)

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9. C. Holden, Science J Z2 1066 (1985). 10. M.J.K. Harper, in "Research on t h e Regulation of Human FertilitytT,VoL 1, E. Diczfalusy and A. Diczfalusy,'Eds, Scriptor, Copenhagen, 1983, p. 250-267. 11. K.E. Kendle, in "Antihormones", M.K. Agarwal, Ed., Elsevier/North Holland Biomedical Press, Holland. 1979,.pp. 293-305. M.K. Agarwal, Ed., Walter de Gruyter, New York, 1982, 12. K.E. Kendle, in "Hormone Antagonists", pp. 233-246. 13. D. Philibert. R. Deraedt a n d G. T e u b c h , Abstracts of Papers, 8 t h International Congress of Pharmacology, Tokyo, July 1981, Abstract 1463. 14. E. Sakiz and G. Azadian-Boulanger, in f'Hormonal Steroids. Proceedings of t h e Third International Congress on Hormonal Steroids." International Congress Series No. 219, V.H.T. J a m e s e n d L. Martini, Eds., Excerpta Med. 1971, 865-871. "aulieu, C.R. 15. W. Herrmann, R. Wysq A. Riondel, D. Philibert, G. T e u b c h , E. Sakiz and E.E. Acad. Sc. Paris 294, 933 (1982). 16. D. Shoupe,C. Osborn, P. Lahteermaki and D.R. Mishell, Jr., Abstracts of Papers, 67th Annual Meeting, The Endocrine Society, Baltimore, MD, June, 1985, Abstract 641. 17. L. Kovacs, M. Sas, B.A. Resch, G. Ugocsai, M.L. Swahn, M. Bygdeman and P.J. Rowe, Contraception 3 399 (1984). 18. M. Bygdeman and M-L. Swahn, Contraception 3 45 (1985). Baulieu, in "Abortion: Medical Progress and Social Implications", Ciba Foundation 19. E.-E. Symposium 115, R. P o r t e r a n d M. (YConnor, Ed%, Pitman, London, 1985, pp. 192-210. 20. G.D. Hodgen, Fertil. Steril. 3 263 (1985). 2 1. D.L. Healy, E.E. Baulieu and G.D. Hodgen, Fertil. Steril. 3 253 (1983). 22. H.B. Croxatto, A.M. Salvatierra and I.M. Spitz, 67th Annual Meeting, T h e Endocrine Society, Baltimore, MD, J u n e 1985, A b s t r a c t 620. 23. X. Bertagna, C. Bertagna, J-P. Luton, J-M. Husson and F. Girard, J. Clin. EndocrinoL Metab. 3 25 (1984). 24. D.L. Healy, G.P. Chrousos, H.M. Schulte, R.F. Williams, P.W. Gold, E.E. Baulieu and G.D. Hodgen, J. Clin. Endocrinol. Metab. 3 863 (1983). 25. R.C. Gaillard, A. Riondel, A.F. Muller, W. Herrmann and E.E. Baulieu, Proc. Natl. Acad. Sci. U.S.A. 3879 (1984). 26. A. Gravanis, G . Schaison, M. George, J. DeBrux, P.G. Satyaswaroop, E.E. Baulieu and P. Robel, J. Clin. Endocrinol Metab. 156 (1985). Baulieu, 6 7 t h Annual 27. G. Schaison, N. Lestrat, B. Couzinet, J. de Brux, P. Bouchard and E.E. Meeting, The Endocrine Society, Baltimore, MD, June, 1985, Abstract 621. 2236 (1985). 28. K.B. Horwitz, EndocrinoL 29. G. Teutsch, in "Adrenal Steroid Antagonism", M.K. Agarwal, Ed., Walter d e Gruyter, New York, 1984, pp. 43-71. 30. G. Neef, S. Beier, W. Elger, D. Henderson and R. Wiechert, S t e r o i d s 9 349 (1985). 31. H.P. Schane and J.E. Creange in "Research Frontiers in Fertility Regulation", G.I. Zatuchni, M.H. Labbok, and J.J. Sciarra, H a r p e r and Row, New York, N.Y., 1980, pp. 330-343. 32. R.G. Christiansen, H.C. Neumann, U.J. Salvador, M.R. Bell, H.P. Schane, Jr., J.E. Creange, G.O. Potts, and A.J. Anzalone, J. Med. Chem. 3 928 (1984). 33. Z.M. van der Spuy, D.L. Jones, C.S.W. Wright, B. Piura, D.B. Paintin, V.H.T. James, and H.S. Jacobs, Clin. Endocrinol. 521 (1983). 289 (1981). 34. J.E. Creange, A.J. Anzalone, G.O. Potts, a n d H.P. Schane, Contraception 479 (1985). 35. B.W. Snyder and H.P. Schane, Contraception Gilmer, Fertil. Steril. 3 36. N.S. Pattison, M.A. Webster, S.L. Phipps, A.B.M. Anderson, and M.D.G. 875 (1984). 37. L. Birgersson and E.D.B. Johansson, Acta Endocrinol. (Copenhagen) (suppl 256), 145 (1983). 788 38. D.A. Marsh, H.J. Brcdie, W. Garrett, C.-A. Tsai-Morris, and A.M.H. Brodie, J. Med. Chem (1985). 1006 (1978). 39. R.W. Brueggemeier. E.E. Floyd, and R.E. Counsell, J. Med. Chem. 40. P.A. Marcotte and C.H. Robinson, Steroids% 325 (1982). 365 (1978). 41. A.M.H. Brodie, J-T. Wu, D.A. Marsh and H.J. Brodie, BioL Reprod. 42. A.M.H. Brodie, J-T. Wu, D.A. Marsh, and H.J. Brcdie, EndocrinoL 104,118 (1979). 43. D. Pavara, U. Guzzi, R. Ciabatti, F. Battaglia, A. Depaoli, L. Gallico, and G. Galliani, Prostagland i n s % 3 1 1 (1983). 44. US. P a t e n t 4,372,973 (1983); C.A. 99: 5432w. 45. P.A. Grieco, W. Owens, C.-L.J. Wang, E. Williams, W.J. Schillinger, K. Hirotsu, and J. Clardy, J. M e d Chem. 3 1072 (1980). 46. T.K. Schaaf, M.R. Johnson, J.W. Constantine, J.S. Bindra, H.-J. Hess, and W. Elger, J. Med. Chem. -62 328 (1983). 47. B.J. Broughton, M.P.L. Ceton, A.J. Christmas, E.C.J. Coffee, and D.J. Hambling, Prostaglandins -2! 53 (1981). 48. M. Hayashi, Y. Arai, H. Wakatsuka, M. Kawamura, Y. Konishi, T. Tsuda, a n d K. Matsumoto, J. Med. Chem. 3 525 (1980). 49. J. W. Wilks, Science 221. 1407 (1983). 50. J.W. Wilks, N.A. Nelson, Prostaglandins 3 323 (1984). 51. J. A. McCracken, M.E. Glew, S.S. Hull, Jr., L. Bovaird, L. Underwood, and J. Fried, in "Advances

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in Prostaglandin and Thromboxane Research," VoL 6, B. Samuelsson, P.W. Paoletti, Eda, Raven Press, New York, NY, 1980, p.365.

Ramwell, and R.

Chap. 17 52. 53. 54. 55. 56. 57. 58. 59.

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E. diSalle, R. Ceserani, M.G. Dell Isola, F. Faustini, A. Panzeri, a n d C. Gandolfi, A b s t r a c t s of Papers, V International Conference Prostaglandins, Florence, 1982, A b s t r a c t No. 421. K. Green in "Prostaglandins and Fertility Regulation", M. Toppozada, Ed., MTP Press (ref. is incomplete), 1984, p.11. G.L. Bundy, D.C. Peterson, J.C. Cornette, W.L. Miller, C.H. Spilman, and J.W. Wilks, J. Med. Chem. 3 1089 (1983). M. Bygdeman in "Research on t h e Regulation of Human Fertility", Vol. 2, E. Diczfalusy and A. Diczfalusy, E d r , Scriptor, Copenhagen, 1983, pp. 528-543. H. Schnieden in "Progress Towards a Male Contraceptive", S.L. J e f f c o a t e and M. Sandler Eds., John Wiley and Sons, Ltd. Chichester, U.K. 1982, p. 227. J.P. Pryor in "Progress Towards a Male Contraceptive" S.L. J e f f c o a t e and M. Sandler, Eds., John Wiley and Sons, Ltd. Chichester, U.K. 1982 p. 135. P. Franchirnont, J. Verstraelen-Proyard, M.T. Hazee-Hagelstein, Ch. Renard, A. Demoulin, J.P. Bourguignon, and J. Hustin, Vitamins and Hormones 243 (1979). C.H. Li, R.G. Harnrnonds, Jr., K. Rarnasharma, and D. Chung, Proc. NatL Acad. Sci. USA & 4 0 4 1

(1985). 60. D. Yamashiro, C.H. Li, K. Ramasharma, and M.R. Sairam, Proc. Natl. Acad. Sci., USA. 5399 (1984). 61. S.-Z. -Qian and 2 . 4 . Wang, Ann. Rev. Pharmacol. ToxicoL 24 329 (1984). 62. H.H.S. Fong in "Natural Products and Drug Development", P. Krogsgaard-Larsen, S. Brogger Christiansen, H. Kofod, Eds. Munksgard, Copenhagen, 1984, p. 355. 63. G.-2. Liu, K.C. Lyle and J. C a o in "Endocrinology, Proceedings of t h e 7th International Congress

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of Endocrinology", F. Labrie and L. Proulx, Eds. Elsevier Science Publisher, B.V. Amsterdam, T h e Netherlands, 1984 p. 227. 64. I.C. Kim, D.P. Waller, G.B. Marcelle, G.A. Cordell, H.H.S. Fong, W.H. Prikle, L. Pilla and S.A. 253 (1984). Matlin, Contraception 65. S.A. Matlin, R. Zhou, G. Bialy, R.P. Blye, R.H. Naqvi, and M.C. Lindberg, Contraception 141

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(1985 1. 66. S. Toovey, E. Hudson, W.F. Hendry, and A.J. Levi, G u t % 445 (1981). 67. A.J. Levi, S. Toovey, P. Smethurst, and B. Andrews in "Progress Towards a Male Contraceptive", S.L. J e f f c o a t e and M. Sandler, Eds. John Wiley and Sons, Ltd., Chichester, U.K. 1982, p. 209. 68. C. Pholpramool and A. Srikhao, C o n t r a c e p t i o n s 273 (1983). 69. G.F. Paz, M. Shilon and Z.T. Homonnai, C o n t r a c e p t i o n 3 189 (1984). 70. Z.T. Homonnai, M-Shilon, and G.F. Paz, Contraception 3 479 (1984). 71. G. Galliani, A. Assandri, L.J. Lerner, A. Ornodei-Sale, G. Lancini, P.E. Nock and A.M. Grant, Contraception 165 (1982). 72. G. Galliani, A. Assandri, L. Gallico, F. Luzzani, C. Oldani, A. Ornodei-Sale, A. Soffientini, and G. Lancini, Contraception 3 163 (1981). 73. D. Barone, A. Assandri, and G. Galliani, IRCS Med. Sci. 3 442 (1984). 74. J.A. Clemens, M.E. Flaugh, J. Parli, and B.D. Sawyer, Neuroendocrinology 83 (1980). 75. R.M. Kanojia, E. Chin, C. Smith, R. Chen, D. Rowand, S.D. Levine, M.P. Wachter, R.E. Adams and D. Hahn, J. Med. Chem. 3 796 (1985). 39 (1984). 76. D.W. Hahn, A.J. Tobia, M.E. Rosenthale, and J.L. VcGuire, Contraception 77. M. Marko and D. Romer, Life Sci. 233 (1983). 379 (1980). 78. J.R. Fozard, M.-L. Part, N.J. Prakash, and J. Grove, Euro. J. of PharmacoL 79. G. Galliani, G. Colombo, and F. Luzzani, Contraception 3 159 (1983). 80. C. Tietze, "Induced Abortion, A World Review, 1983", 5 t h ed., T h e Population Council, New York, N.Y., 1983. 81. S. Gombe, E a s t Afr. Med. J., 3 203 (1983).

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Chapter 18. Chemical Control of Androgen Action Gary H. Rasmusson Merck Sharp & Dohme Research Laboratories, Rahway, NJ 07065

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Introduction Androgens originate primarily from three glands: the testes, the adrenal cortex and the ovary. The primary androgen from the testes is testosterone (T), while the weakly hormonal androgens, dehydroepiandrosterone (DHEA), its sulfate ester and ndrostenedione, are the primary C19 steroids secreted by the adrenal a n d ovary! Each gland appears to secrete its products with a circadian variation corresponding to some degree with the secretions of stimulatory proteins from the pituitary. The release of these proteins, primarily luteinizing hormone (LH) [also interstitial cell stimulating hormone (ICSH) or lutropin] for the testisovary and adrenocorticotrophic hormone (ACTH) for the adrenal, in turn, is controlled primarily by hypothalamic factors, l u teinizing hormone releasin hormone (LHRH) and corticotrophic releasing factor (CRF), respectively. Testosterone and its metabolites, estradiol and 5 cx-dihydrotestosterone (DHT), in a feed-back role a r e able to influence LH release a t the neural a n d pituitary levels. The release of ACTH is sensitive to the levels of circulating cortisol.' Thus, the androgen level in a n individual is dependent on a balance of several interrelated stimulatory a n d inhibitory processes. The end organ response to androgens, including that of feed-back control, is mediated through the androgen receptor (AR) which acts in the cell a t the nuclear level to modulate R N A synthesis.* The nuclear AR has been found to be associated with only two natural androgens, T or DHT. DHT binds more avidly to the AR than T and, in certain tissues. such as the rat prostate, DHT is the exclusive androgen present in the nuclear isolates. Testosterone is derived from DHEA and androstene-dione the biosynthetic steps of 3 p -01 dehydrogenasel A 5,4-isomerase and 17 p -01 oxidoreductase; DHT is formed irreversibly from T by the membrane bound enzyme 5 % -reductase. Genetic deficiencies in androgen-synthesizing enzy es or in the AR result in development of male fetuses with female characteristics? Likewise, female fetuses are virilized by exposure to androgen. Excess androgenic activity is implicated in precocious puberty, male hypersexuality, seborrhea, acne, male pattern baldness a n d hirsutism. Prostate size and maintenance are androgen dependent, suggesting that interference with this hormone would be a treatment f o r benign prostatic hyperplasia (BPH) and prostatic carcinoma (PC). Male fertility control would be possible if T-stimulated spermatogenesis could be blocked. Treatments which interfere with androgen action include administration of agents that block regulatory mechanisms, the A R or key The study of androgen biosynthetic steps in the formation of T or DHT. antagonists is over 20 years old and i t is only recently that clinical use of these agents has been extensively investigated. This review will discuss recent Additional developments in methods f o r lim'ti g and abolishing androgen &tion. information on androgen actioni-' and androgen antagonists is available in several books or reviews.

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INTERFERENCE WITH CONTROL REGULATORY MECHANISMS Estrogens - Estrogens are the natural antagonists of androgens. Increases in circulating strogen levels generally result in reduced levels and availability of andro ens.18 Estradiol interferes directly with T production a t the testicular level.' Circulating levels of the testosterone binding globulin increase on stimulation, causing less free T to be available f o r cellular uptake. pharmacological levels, estrogens block the secretion of LHRH and LH and, thus, ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21

Copyright 0 1986 by Academic Press, Inc. All rights of reproduction in any foim reserved.

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the production of T in the testes. This method of chemical castration has been used f o r years as a non-surgical treatment of PC. The side effects of gynecomastia, loss of libido, liver toxicity and, more seriously, cardiovascular complications are common to estrogen treatment. Diethylstilbestrol (DES), ethinyl estradiol and the estradi -conjugated mustard, estramustine phosph te (1,Emcyt ), have been used in DES only slightly decreases the the treatment of PC.h production of adrenal androgens but may actually potentiate their ff$tion i n PC by increasing prostate levels of AR. The cyclotetrasiloxane 2 (quadrosilan, CisobitanR) in a PC trial exerted the same responses, therapeutic and toxic, as other estrogens. 15

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Proaestins - Progestational steroids also reduce the effects of androgens. Several modes of actp&iave been postulated the primary mechanism being inhibition of LH secretion. In addition, seve 1 progestins bind competitively with the AR to reduce the end-or n response O’ ‘ ‘ and some ve been shown to modify androgen biosynthesis!’ metabolism and clearance!’ The progestins generally appear to be free of the gynecomastia and cardiovascular side effects found with estrogens although loss of libido has bee o erved. S e 1 progestins have been and PC. The results, although tested in the clinic for treatment of BPH encouraging, have not been significant enough to replace other means of treatment of these conditions. T he gonadotropin inhibitor daaazol (3severely sup essed T levels in a PC trial, but did not affect the course of the disease. The progestational antiandrogen, cyproterone acetate will be discussed below.

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L H R H a n a o la ~ These agents were reviewed i n Volume

20 of t is series3’ and the proceedings of an international symposium were published!’ The fact that continuous, non-pulsatile dosing of the agonist form of these agents provides a mild, reversible means of chemical castration has led to their widespread clinical use for PC. After dosing, the initial surge of T secretion falls to castrate levels. T he effect on the course of the disease appears as good as estrogen treatment without the d libido occ gynecomastia or cardiovascular side effects. Loss f fertility one might expect. Successful trials with buserelin?’ leuprolide” and Zoladex have been reported. Added benefits appear to be gained by combining LHRH agonists with anti-androgens or androgen biosynthesis inhibitors (see below). Administration of buserelin to male dogs treated daily with percutaneous T or D is reported to result in azoospermia without loss of libido or prostatic function. Similar studies in man with nafarelin and the depot androgen, testosterone enanthate, result i n a lowering of sperm count in 5 of 6 subjects, but azoospermia was not attained.

w 31 5T

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T e LHR antagonist RS-68439, [N-Ac- oNal(2)l, DpC1-Phe2, D -Trp3, D hArg(EtZ) , D -Alar o]LqFH,rapidly suppressed pituitary and testicular function in Ejaculatory function with continued azoospermia could rats, dogs an d monkeys. be maintained by T supplementation in dogs treated with RS-68439.

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Chap. 18

Chemical C o n t r o l of Androgen Action

Rasmusson

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ANDROGEN RECEPTOR (AR) ANTAGONISTS Flutamide a n d Non-steroidal Antazonists - Of the non-steroidal antiandrogens, flutamide (a has been the most widely studied. It a is "pure" antiandrogen since i t appears to have a single mode of action, interference with activated AR-complex formation in target cells. So e f the pharmacology and clinical experience with flutamide has been reviewed. lutamide is metabolized to the more active ochydroxy derivative 5. (Sch 16423)4F Topical or oral administration of f l amide reduces androgen-dependent sebaceous gland activity in rats and hamsters!' The topical effect is not confined to the application area but affects remote sites as well. In humans treated with & th sebum secretion rate is affected differently between males (-) a n d females Although plasma levels of T rise a f t e r flutamide dosing as a result of a block to the feedback ef ct of T, the cellular levels of T a n d DHT are reduced in androgen target tissues!' Clinical studies for treatment of BPH with flutamide were inconc sive a n d pointed out the need f o r Extensive trials f o r treatment of better indices of improvement in this dis PC with flutamide have been conducted. f8*''*46 In general, results equivalent to those seen with castration or DES treatment were found. Side effects were primarily breast tenderness a n d gynecomastia. More positive results f o r PC treatment have been a t ned with flutamide used in combination with LHRH agonists or orchiectomy!' The anti-androgen reduces the effect of the early T surge caused by the agonists a n d also neutralizes the effect of circulating nontesticular androgens. The objective response rate was very high relative to castration alone. Side effects were hot flashes a n d diminished libido.

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CF; -0-b-

R

The related anti-androgen 1 (RU 22208, AnandronR) which has pharmacological properties similar to flutamide, effect' ely blocks the trophic effects of adrenal steroids in castrate- or DES-treated rats.@ In a human PC study -7 with a LHRH agonist or with orchiectomy, resulted in significant improvement symptoms over prior therapy. However, 'n prolonged studies, 1 caused visual problems and was replaced with flutamide4' Topical treatment of hamsters with 8 (RU 22930) was as effective as or 2 in blocking T-stimulated f l a n k organ growth but w h j t given subcutaneously, showed little effect on T-stimulated prostate growth. The tetra loro- o< -hydroxyisobutyranilide 6 (AA560) resembles flutamide i n its a c t i o n j P A series of potent anti-androgenic hydroxyflutamide th steroidal and non-steroidal antianalogs have been prepared and compared androgens f o r i n vitro a n d in vivo activity?' No correlation of biopotency and receptor binding affinity (RBA) could be determined. However, some analogs a t a high dose stimulated castrate rat prostatic growth indicating that agonist activity can be obtained with non-steroidal agents. Anti-androgenic activity can be retained when an olefin, %q,etylene or cyclopropyl group is substituted f o r the amide moiety of such anilides. Non-steroidal anti-androgens outside the flutamide class a r e rare. The antiulcer agent cim tidine, is a weak AR antagonist which occasionally induces gynecomastia in man.94 When given to hirsute women over a 3 month

182

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- Metabolic Diseases and Endocrine Function

Pawson, Ed.

period, cimetidine showed a beneficial effect on hair growth.55 The anti-estrogen raloxifene (2,LY-156758) also has andr en antagonist properties and has potential for use as a dual-acting agent in BPH' The DES-like a i-androgen bifluranol, (1p)showed some desirable effects for treatment of BPH.' The phthali 'de 11 (DIMP) is a weak anti-androgen which was active in standard animal assays.3 HO

OH

11

19

-

Cvmoterone Acetate ( 121 The most thoroughly studied androgen antagonist is cyproterone acetate. Systematic studies over the last 24 years have resulted in its applicatio&!tf treatment of most androgen related disorders. Several reviews are limits androgen action available. Whereas the parent alcohol, cyproterone (D, primarily by interference at the level of the AR; the acetate l2,a potent progestin, , acts as a gonadotropin inhibitor and enhances the clearance of blocks the testosterone.@ In man, 12 is metabolized to it 15 p -hydroxy analog fi which can occur at levels twice that of 12 in plasmai3 and which retains the androgen ~~ ofits potential for antagonist activity of U but is a less potent p r ~ g e s t i n . Because fetal feminization 12. is often administered in combination with ethinyl estradiol as a contraceptive regimen. This combination has found extensive use as a treatment for hirsutism in women. Effec on hair growth (hirsutism or aloggcia) in females require 3-9 months to developdS while noticeable effects on acne and seborrhea appear earlier and seem more sensitive to treatment. Treatment of acne in males with oral 12 is effective but side effects f gynecomastia, loss of libido and spermatogenic defects have been observed. ''?en topically applied, eff tive and is associated with systemic effects!' Trials of J.2 in BPH PC% have shown qualitative degrees of success but have not gained wide acceptance. recent s t q e s in which is combined with DEFfeor buserelin have given preliminary indications of being better treatments for PC. Some success has bee observed in male breast Precocious puberty cancer treated with 12.3' in boys and girls has been treated with 12. although interferenft with adrenal function was seen Suppression of hypersexual't in this age group. B X in men with is more effective than castration. $1 Spermatogenesis is inhibited by & but its us for COCH3 H male contraception does not seem promising. 95 u H H fi C O C H ~ OH 17 l3 -Hvdroxvsteroidg A number of 17-oxygenated steroids have shown androgen antagonist activity. Probably the most thoroughly studied is the aldosterone In early studies, development of gynecomastia antagonist spironolactone ibition a t the occ rred in patients after prolonged use. A dual mode of action, AR96 and interference with the 17-20 side-chain cleaving enzyme,vis thought to provide the primary means of androgenic deprivation. When 15. was g'ven to castrated PC patients, plasma levels of adrenal androgens were reduced!' In several t dies, a beneficial effect for 15. in treating hirsutism and acne in 7J-t1 was found, although in a comparative study, fi was not superior to gBenAdditional benefit may be derived by using a combined regimen of with

-

(m.

Chemical C o n t r o l of Androgen Action

Chap, 18

Rasmusson

3

an oral contraceptive or dexamethasone. 83-84 Topical applicatio of 15.has shown a local anti-androgenic effect on the male hamster flank organ!5 The spiroether 16 (MK-316), which combines soy8 structural features of 12 a n d fi is effective in reducing the size of dog prostate.

15

9

By manipulating the bulk a t the 16-position of 19-nortestosterone, optimal androgen antagonism and minimal trophic effects were obtained with the 1 6 p -ethyl lone). Reviews and a comprehensive report of derivative 11 (TSAA-291, o studies with 1z have appeared. This material binds to the androgen receptor modest with a n apparent K i of 7 x 10- 8M and is inhibitor of the enzyme 5 K-reductase?' The effects of 11on gonadotropins is a typical, being slightly inhibitory in male and stimulatory in female rats. In the dog, no effect on T levels is seen but the prostate is reduced in size. In a number of clinical studies f o r treatment of BPH with injected weekly, improved symptoms wi 17 a minimum of side effects have been observed.9 1-49

"-

u,

Additional bulk a t the 1 7 ~ - p o s i t i o nof testosterone as, f o r example, with the 17a - 8 ~ o p y l derivative 1_8 (topterone) resulted in a n effective androgen antagonist. This material blocks the actions of T and DHT by topical and systemic administration. In recent experiments, the 17 oc-propyl analog (SH-434) of the potent androgen mesterolone 20 as only locally active as a n anti-androgen on topical administration to hamste?' When applied topically to humans with acne a n d seborrhea f o r a n average of 3 months, 19 effective1 reduced sebum No effect on excretion by 23-60% a n d improved symptoms in 11 of 13 patient serum hormone levels was found; 19 is in Phase 1 clinical trials. 1

b

A number &t 17 p -hydroxy-des-A-steroids have been assayed f o r androgen antagonist activity. As was the case with other pure anti-androgens, their interaction with the AR was more labile than that of T or DHT. For A R binding, the equivalent of the C-l of a steroid must be present i n these molecules a n d planarity of the C-10 to C-12 edge increases activity. An anti-acne clinical candidate developed from this series, 21. (RU 38882), given orally or S.C. to rats, had less than 1/25 the androgen antagonist activity of but on topical application i t was 100-fold more active in regicing sebaceous elements i n the same animal without showing systemic effects. A des-D-19-nortestosteroneanalog 22 (Ro 52537) topically educed sebum production in humans better than some steroidal anti-androgens. 94

184

S e c t i o n IV

- Metabolic Diseases and Endocrine Function

Pawson, Ed.

Addition of methyl groups alpha to the carbonyl of the potent androgen 22 (R 1881) converted the compound into the anti-androge 4 (R 2956). This material which blocked androgen action in rats a n d dogs,"'was not a 5 oc-reductase inhibitor but exhibited weak gonadotropin inhibition in female rats. B-norMethyltestosterone (22) is a n androgen antagonist whic has shown a beneficial clinical result for acne and hirsutism after oral dosing." Weak anti-androgenic activity in l v p e has been recently reported f o r the cyclopropyl analog 26 of testosterone.

(m

Y

25

2 H CI OH OH

1 1-Oxvnenated Steroids - Several steroids which topically reverse androgen stimulated skin conditions but have shown little or no anti-androgenic effects on systemic administration include the 1 I-oxygenated steroids 27-30. Long-tcrm studies in humans indicatc&that sebum production and hair loss could bc reduced by treatment with 22. The 11-oxosteroid was the best of several such 17sulfinyl steroids 'n blocking androgen-regulated hamster flank organ growth a n d lipid synthesis."' The two carboxysteroids 29 (Org 7294) and (Org 7476) are not 5 ocir&luctase inhibitors, but reduce T- and not DHT-stimulated sebaceous gland growth.

BIOSYNTHESIS INHIBITION

-

(m,

a n antifungal drug which prevents ergosterol 17.20-Desmolase Keto o azole biosynthesis i n fungi,'" is a potent inhibitor of the cleavage reaction which converts 17 oc - ydroxy progesterone to androstenedione, the penultimate step i n T biosynthesis."' Treatment of humans with 2 resulted in a n im ediate decrease in C I 9 steroids but feedback effects tended to reverse this process." At constant,

Chap. 18

Chemical C o n t r o l of Androgen Action

H

Rasmusson

185

-.

-

high df&s, a reduced androgen level was maintained a n d led to beneficial effects in PC. The advantage with this treatment is that both adrenal a n d testicular androgen synthesis a r e blocked with only moderate e fects on corticoid production. The use of 21 with the LHRH analog Zoladex‘ in PC patients who failed tplbespond or relapsed on conventional hormone therapy has shown The successful use of promise. in precocious puberty has been reported. 1

fTme

3 B -01 Dehvdroaenase - Although inhibition of this enzymic step could prevent the conversion of DHEA into androstenedione and, thus, into T i t is of more consequence in the production of progesterone from pregnenolone (see Chapter 17 of this volume). 5 ci-Reductase - In many androgen target tissues, most notably the prostate a n d skin, T is largely converted to DHT, which is the trophic hormone in these tissues. Agents which prevent DHT formation should be selective anti-androgens which would not interfere with independent actions of T on muscle or in the brain. In early in vitro with a n oxygenstudies with human skin 5a -reductase, 3-keto-A4 steroi Additional studies containing 17 p -side chain were effective enzyme inhibitors.’” with the non-hormonal 17 p -carboxy-4-androsten-3-one (32) on the female hamster flank organ or i n the castra e mouse indicated that T- but not DHT-stimulated Progesterone (Xi) is a potent 5 a -reductase growth could be attenuated.‘ I 3 inhibitor which is extensively metabolized in the skin. When topically a p lied, 33 selectively and locally blocks T and not DHT stimulation in hamsters. ‘14 On human skin, 5 o< -reductase is completely blocked byljopical 22 but skin areas remote from the application site may be affected. excretion was seen in women but not men in one study with while in another study 85% of the men responded with decreased excretion.

A structural activity (SAR) stu of 4-azasteroids as inhibitors of rat Optimal jn vitrq activity resides with prostatic 5 ci-reductase has been 4-methyl-3-0x0-4-aza-5 o( -androstanes substituted in the 17 -position with a semipolar group. Examples of these compounds have been found to inhibit the 5s reductases of rat prostate, pituitary, hypothalamus, liver a n d i t r i ial cells, human prostate and skin, dog prostate and hamster sebaceous gland. ‘18-f’’ Oral or S.C. administration of 4-MA to rats decreased the DHT content of the prostate was more cffective in blocking T while T levels rose. 126 In castrate rats stimulated prostate growth than that stimu by DHT. Reduction in dog prostatic size has been demonstrated with &“’p28 The rate of growth of a rat PC,$vmor was slowed to that equivalent to castration by administration of 2 or s. Azaster1fdp6-13ty ‘ds 4 3 and 26 caused fetal feminization of offspring of treated zasteroids unsubstituted on the ring nitrogen have very low pregnant rats. affinity f o r the AR. oxazasteroid 2 is a poorer 5 a< -reductase inhibitor than the parent azasteroid?” The 4-chlorosteroid 3 was the best (K-=95n several 2- and 4-substituted steroids for inhibition of rat prostatic 5 K-reductase.

(w

930s

186

Section I V

- Metabolic

Diseases and Endocrine Function

Pawson, Ed.

R

k R-1 C02H COCH3 CH(CHz)CH20H COCH3 COCH3

R2 H H H H OAC

Other

4- CI 6=CH2 63CH2

x H ZZ

36

CH2 CH2 CH2

37 0

S

Y -

NCH3 CONEt2 NCH3 CH(CH3)COzNo NH CON(i-C,H,)2 NCH3

CH2

-R

CN2

CH(CH3)CH20H CH(CH3)CH20H

A number of irreversible inhibitors of 5 a -reductase have been reported. addition of a 6-methylene group to 3-keto- d steroids

a

reduced rat prostate growth. The parenterally 5,lO-secosteroids 41 and 42, also apparent Michael acceptors, appear to be irreve le inhibitors of When given rat epididymal 5 a-reductase. topically, 42 blocked th effects of T on the female hamster flank organJ4' The 4-diazo-5 a-steroid is a selective irreversible inhibitor MDL-18341 of 5a-reductase (Ki = 35 nM) with no affinity f o r the DHT-Tfiabolizing enzyme 3 a-hydroxysteroid oxidoIn castrate rats, 42 b o ed T but not reductase. DHT effects on sex accessory glands. The T effect on growth of the levator a n i was not antagonized by 43.

The

'"

(a

"'

41

R=O R=COCH3

Conclusion T h e development of agents which will limit or block androgen action is reaching new levels of refinement. The use of LHRH analogs, alone or in the presence of androgen antagonists or synthesis inhibitors, now provides a highly effective a n d safe alterntive to surgical castration in the treatment of PC. Idiopathic hirsutism often responds favorably to anti-androgen treatment but development of agents f o r the treatment of non-life threatening ailments such as skin disorders or BPH has been slow because of the potential f o r hormonal side effects, slow or erratic onset of action, alternative medical or surgical methods a n d which show local a lack of appropriate experimental models. The use of 19. and topical effects with negligible systemic activity in animal models, is a n example of recent attempts to develop treatments which are safe and selective in their action. Similarly, the new 5 a-reductase inhibitors afford a class of compounds which may be free of some side effects associated with classical anti-androgens. Such targeting of inhibitors to specific tissues or enzymes has the potential to provide therapeutic agents which can be used safely on a much larger scale than was possible in the past.

Chap. 18

Chemical Control of Androgen Action

Rasmusson

187

Referencq 1.

2.

3. 4. 6. 6.

7. 8. 9. 10. 11. 12.

13. 14. 15. 16.

17.

18. 19.

20. 21. 22. 23. 24.

25. 26 27 28 29

so 31

32 33 34 35 36. s7. 58. SO.

40.

D.B. C o r m in "Biochemistry of Steroid Hormones," 2nd Ed., H.L.J. Makin, Ed., Blackwell Scimtiflc Publications, Oxford, 1984, Chapter 6, 7 and 8. 9. Liao and R.A. Hiipakka in "Biochemistry of Steroid Hormones," 2nd Ed.,H.L.J. Makin, Ed., Blackwell Scientific Publication., Oxlord, 1984,.Chapter 17, R.V. Broob in "Biochamiitry of Steroid Hormones," 2nd Ed.,H.L.J. Makin, Ed.,Blackwell Scientific Publicationi, Oxford, 1984, Chapter 16. J.H. Clark. W.T. S c h r d e r and B.W. O'Mdley in 'Textbook of Endocrinology," 7th Ed.,J.D. Wlllon and D.W. Foiter, Eda., W . 6 Saund.rm.Phildelphia, 1986. I,. Martini and M. Motta, Eds., "Androgens and Antiandrogeru," Raven P n u , New York, 1977. D.J. Tinddl, C.H. Chang, T.J. Lob1 and. C.R.Cunninghun, Phumac. Ther., 24,sB7 (1984). M.K. A g u r d , Ed., "Antihormonn," Eluvier North/Holland, Amstordam, 1979, p. sB1. J.P. Bercovici in "Antihormow," M.K. Aguvd. Ed..Elmvier North/Holland. Amstordun, 1979 p. SOT. M.K. Aprwd. Ed.,"Hormone Antyoniat.," W d t u deGruyter. Berlin. 1982. R.Msrcue and 9.0. Konnman, Annu. Rev. M d . , 567 (1976). T.M. Jones. V.S. Fang, R.L. Landau and R. Rmenfield. J. Clin. Endocrinol. Metab., 1568 (1978). C.W. Burke and D.C. Anderson, Nature. 58 (1972). J.T. Grayhack and J.M. Koslowrki, Urol. Clin. North Anur., 1.659 (1980). M.Moguilewiky, C. Tournunine and 1. Fiet. 1. Stemid Biochmm., 9Suppl., 175 (1p86). T. Kruup, F. R u m u r a n and P A . Gunmolga.ud, S c a d . J. Urol. Nephrol.. Q. 11 (1978). R. Rangno. 1. Antonipillai, B. Guyda and B. Murphy, Clin. Ru..=,'IsS (1974). J. Celler, J . Albert, 9. Geller, D. Lopes, T. Cantor and S. Ym, J. Clin. Endocrinol. Metab.. 1000 (1976). H.Steinbeck, S.H.H u m , K.J. G r d and F. Neumann. Act. Endocrinol., B$ Suppl. 208, 66 (1977). 1. Mowsaovics, D.E. Biehr, K.W. Chung, L.P. Bullock and C.W. Bardin, Endocrinology, 1589 (1974). F.Onstano, K. Bandhauer and J.E. Altwein, Urnloge.. 269 (1974). 0. Sufrin and D.S.Coffey, I n v r t . Urol., s,1 (1976). A.L. Southnn, 0.0. Gordon, J. Vittek and K. Altman in 'Androgens and Antiandrugma," L. M&ini and M. Motts, Eds.. Raven P m u , New York, 1977, p. 165. J . Geller, A. h d t , K. N&w and H . Newmm, J. Am. M d . h c . , 1421 (1989). R.E. Rangno, P.J. McLwd, J. R u d y and R.I. Ogilvie, Clin. Pharmuol. Ther., 12,668 (1971). D.A. Aubrey and T. Khosla, Brit. J . Burg., 648 (1971). 0 . Yoihida and K. Okada, Cum. Ther. R r . , E, 139 (1984). J . Geller, J . Albert and S.S.C. Yen, Urology, 12,5S7 (1978). F.H.Schroedar, The Promtat*, 1,19s (1984). P.O. Hedlund, D. F m d m a n , P. h p o s t i , S. Genhagen and K. Camtrom, The Prostate. 1,S47 (1906). A.S. Dutta and B.J.A. Furr, Annu. Rep. Med. Chem., 203 (1986). P.R.K. Raddy and M.L. Dufau, Edi., J. Stsroid Biochem., 2, (6B) (1986). M. Koutailieris and 0 . Tolis, The Prostate, 1,31 (1986). M A . Vance and J.A. Smith, Clin. Pharmuol. Ther.. Js , 560 (1984). K.J. Walker, R.I. Nicholson, A.O. T u r k u , A. Turkei, K. Crimths, M. Robinson, 2. Criipin M d 9. Drii, Lancet, 413 (1983). Y. Tremblay, A. Bdanger, D. LacMte and F.Labrim, The Prostate, E, S72 (1984). R.S. Swerdloff, D.J. Handelaman and 9. Bhuin, J. Staroid Biochem.. 9 . 8 6 6 (1986). B.H. Vickery, 1. Stuoid Biochem., 77Q (1986). R.O.Neri in 'Androgens and Antiandroguu.' 1.M8rtini and M.Motta. Ed..,Raven Pnu, New York,1977, p. 179. R. Neri and N. K n n m in "Hormono Antyonuti," M.K. Agurd, Ed.,W d t a & Gruytu, Berlin. 1982, p. 247. R. Neri and N. Kumem in"Progmu in C a n m R u e u c h and Th-rwy,"vol. S1. F. Brrciani. at. d.Eds., Raven Pnu, New York. 1984,

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188 86. 86.

87. 88. 89.

w. 91. 92.

93. 94. ~~

96.

97.

Section I V

- Metabolic Diseases

and Endocrine Function

Pawson, Ed.

m,

A. Waiumann, J. Bowdm, B.L. Frank, S.N. H o n i t r and P. Pmst, Arch. Dannatol., 67 (1986). J.R. Brooks, R.D. Brush, D.J. Patanall1 and S.L. Stnlman, P w . Soc. Exp. Biol. Md., l& 647 (1073). R. Nakayuna, K. H i r y a and T. Miki in "Hormone Antagoniiti,' M.K.Aguwd, Ed.,Wdtar do Gnrytar, Naw York, p. 269. P.J. Thorpr, DNO Put., 1,441 (1980). Act. Elldocrind., Suppl. 2% (1919). K.Sudo, K.Yahida, Y. Akinaga and R.Nskayuna, Steroid., g,66 (1901). A. Y u u k a r a , H. Nihira, 8. Matsukl. M. Fujii, H.Fujixua, at d.,Act. Uroi. (Japan), 637 (1984). A. Kondo M. Iiholhi and A. Hirayuna, Niihlnippon J. Uml., (IS, 629,636 (1070). 0.Yoahid., T. Katiumi, Y. Sawunura and M.Sattoh, Acts Umi. (Japan), 499, 609, 621,627(1979). K. Chakrabuty, R.A. Furui, O.C. Dauincua, A.L. Bqler and H.P.Shane, J. Invait. Dannatol., 6 (1980). M. Albring. P. Schummn, C. Okon and A. S c h b m r . Arch. D a a u t . Rr.. 170 (1902). J.B. Schmidt .nd J. Spona, Arch. Dumatol. Ru., 424 (1086). H. Moralai-Alanii. M.-J. Brianna. J. Jwauai. M . 4 . Bouton, L. N d e i r . V. Tonlli and C. Tournamina. J . Mad . Cham

a

a,

a,

a

a,

m,

119861

98 99 100

101. 102. 10s.

104. 106. 106.

107. 108.

109. 110. 111. 112. 11s. 114. 115. 116. 117. 118. 119. 120. 121. 122. 115. 124. 126. 126.

127. 118. 119. 150. 1s1.

132. 133. 154. 155.

136. 1S7. 1S8.

1.99. 140.

141. 142. 143.

hM

179G

'Bouton. D k s p u a , J S r c h r and C Tournamina, J Invait. Darmatol , E, 163 (1986). 19 (1974) J. Tunm. E. Ludwig and U. Volkwain, Arch. Dirm. Fonch , 0. hdian-Boulannr. C BonM. J. k c h i and J.-P. h m d . J. Ph-ol. fpuir). 1.609 (19741. . . A. ZuaW, V.B. M.i;uh and R.B.-Gnanbl~tt,J. Clin. E&ocrinol., ip, 1394 (1dSS). - - 336 (1984). L. Stark., M.Bicikova, R. Hunpl, J. Joika and J. F d k w , C n k . Fum., J. Tunm., M. Seckaimann, U. Volkwain and E. Ludwig, Br. J. Darmatol., 63 (1982). M.J.G m n , R. T i h r i , R.W. Draper, F.E. Cmlon, R.O.Nan andT.T. Kung, J. Mad. Cham., 78 (198s) 329 (1986). I. Clanuchan, H. Dwitt, M.I. Forurua and W.Pisbn, Br. J. of Damatol., M.S. Muriott. J. Om. Micmbiol.. 263 (1010). R.J. Santan, H.YUY den Boucha. J. S m i , J. Brumuu and R. d&wtar, J. CUn. Endocrind. M.tab.. pL, 732 (1985). W. H~YIU, A. Dwhmanl, E. van dar Schuann and G. Varhowan, Act. Endocrinol., 270 (1986). J. Trachtanbrg and A. Pont, Lurcat 11. 453 (1984). 0. Willinnu, J.M. Allan, D. Karla, H.Ware and S.R.Bloom, J. Uml., 2O9A (1984). F.J. H o l l d , 1.FwUnan, J.D. Bulay and A.T.A. F m k u , N. Engl. J. M d . , 1023 (1986). W.Voigt and S.L. ihia, J. Biol. Cham., && 4260 (197s). W.Voigt and S.C. Hka, Endocrinology, 1216 (l97S). A.J.M.Vannorken, C.M.A.A. 0001and H.M.J. Roalob, Br. J. Dermatoi., 456 (1980). A.J.M. Virmorkan, C.M.A.A. Goo1 and H.M.J. Rwloh, Br. J. Darmatol., 696 (1980). N.B. Simpson, P.E. Bowden, R.A.Fontar and W.J. Cunlia, Br. J. Dinnatol., M,687 (1979). A.JM. Varmorken and J.J.G. Houba, D q Intal. CUn. Phum.. 161 (1978). G.H. Rumurron. G.F. Reynolds. T.Utru, R.B. J o h n , R.L. Primka, C. Bunmn and J.R. Brooks, J. Med. Chom.. g,lSWl(1984). T. Lime, C.E. Halia, 9. Ostmva, G.H.Rumwlon and A.H.Chaung, Endocrinology, 1460 (1985). P.J. Bartiu, C.F. Edman and H.J. Kuavolu, Endocrinology, 6S (1984). P.J. Bartici, C.F. Edmm and H.J. KWBVO~M, J. Biol. Cham., 107 (1984). 0 . Varhowan and J. Callaau, J. Stemid Biocham., & S66 (1983). T. Liang, M.A. Cucuri, A.H. Chaung, G.F. Reynoldr and G.H.R u m u w n . Endocrinology. 671 (1085). G.D.B d o v i t s , T.R. Bmwn d C.J. Migaon, J. Andml.. P. 171 (1904). H. S c h d r r , M. Ziagln and M.F.El Etraby, Act. Endocrinol., Suppl. 266, 14 (1983). J.R. Breaks. E M . BaDtista. C. Bennan. E.A. Hun.M. Hichani. D.B.R. Johnston. R.L. Primka. G.H. Rumusion. G.F. Ravnoidi. . . S.M Schmitt an6 G.E. A& Enhocrinology,'lp& 850 (imi). J.R. B w b , C. Buman, M.S.Glitmar, L.R. Gordon, R.L. Primka, Q.F. hynold# and G.H.Rumuilon, The Pmitata. 2, SI (1982). 669 (IWW). U.K. W u ~ d u o t h F.W. , G and J.D. W i h . Endocrinology, N. KdohM. WILiaka, U. Kim, J.P. K w . G.P. Murphy and AA. Sandam, J. Nat. Cancar Irut., 476 (1986). J. Impanto-McGinlay, Z. Binienda, A. Arthur, D.T. Mininhrg. E.D.Vaughan and P.W. Quimby, Endocrinology, 807 (1985). J. Impnto-McGinlay, 2. Binianda, J. Gadnay and E.D. Vaughan, Endocrinology, 132 (1986). J.R. Brook#, C. Bannan, M. Hichans, R.L. Primka, Q.F. hynolds and G.H.Rumuuon, Pmc. 8oc. Exp. Biol. Mad., E ,67 (1982). T. Liang, C.E. Heiu. A.H. Cheung, G.F. b y n o l d i and G.H.Rumuuon, J. Biol. Cham., 714 (1984). P.M. W.intraub, T.R. Blohm and M. hughlin. J. M d . Chun.. fd. U1(1086). F.H. Batwld in "Tha Prodata Call: Structun and Functi.' AIM R. LL., N w Yo&, 1081, p. 269. G.M.Dupuy, K.D. Rohrts, 0. Bieau and A. Chapdaldna, J. Stamid Biocham., 9, 1043 (1978). V. Patmw, T. Wan& L. Lack and A. Sandhrg, Stamids, 1, 121 (1081). 162 (1904). V. Patmw, G.M.Padilla, S. Mukharji and S.A.Marts,J. Pharm. Phumwoi., B. Robun, D.F. Covay, C.H. Robinion and L.L. Ewing, J. Stamid Biocham., 8, SO7 (1977). W. V+, A. C u t m . D.F. COVWM d C.H. Robinwn, k t 8 gndouinol.. 668 (1978). T.R. Blohm. B.W.Mokdf. M.E. Laughlin, A. Sjardma and G.L. &hatman, Biochmn. Bbphys. I*..Com.. po. 27S (1oBo). T. Blohm, M. Laughlin and P.M. Waintraub, Phum.eoloQit, 37s (1906). P h u m a Pmjecti. Nov. 1981,mu 76.

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m,

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Chapter 19. Approaches to Drug Intervention in Atherosclerotic Disease Roger S. Newton and Brian R. Krause. Warner-LambertIParke-Davis Pharmaceutical Research Division, Ann Arbor, MI 48105

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Introduction The progression of atherosclerotic disease from fatty streak to fibrous plaque occurs over decades in most individuals and is initiated or aggravated by risk factors including hypertension, personality traits, genetics, smoking, obesity, age and sex. However, only hypercholeeterolemia has been shown in large scale, double-blind, placebo-controlled clinical trials to be a definitive and sufficient cause for coronary heart disease (CHD). Not only is there a causal relationship between high serum levels of cholesterol (C) and CHD, but reduction of plasma C, in particular low density lipoprotein-cholesterol (LDL-C), can in certain patients result in a decrease in the degree of stenosis of coronary arteries. Since the economic impact of CHD in the United States alone is estimated at $78.6 billion for 1986 (or approximately double the figure for 19781, and that almost 1 million people will lose their lives to heart attack, stroke and other vascular diseases this year, there is an even greater need for new and better approaches toward pharmacological intervention. This review will discuss retmt advances in the regulation of plasma lipids, therapeutic approaches based on cellular C metabolism in specific tissues, and lastly, possible points of metabolic regulation not primarily involving lipid and lipoproteins.

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Abnormalities of Lipoprotein Metabolism The most common monogenic hyperlipidemia. familial hypercholesterolemia (FH), an autosomal dominant tiait that affects both hombzygotes and heterozygotes, was discussed in the previous review by Prugh, et a1.l FH subjects can present with either the Type IIa or IIb phenotype (Table 1). Because of their lack of functional receptors, it is generally believed that FH homozygotes do not respond to dietary or drug treatment whereas heterozygotes with about half the number of receptors do respond. The majority of non-FH hypercholesterolemic individuals probably have a reduced number of hepatic LDL receptors due to such environmental factors as a high dietary intake of saturated fat and C.2 Thus, the LDL receptor has been implicated in virtually all types of hypercholesterolemia (mild, moderate and eve re)^,^ even though its discovery was based on the extremely rare FH homozygous condition. Another possible cause of elevated LDL concentrations is familial combined hyperlipidemia (FCHL), probably the most frequent lipid di~order.~FCHL subjects may or may not have elevated triglycerides (TG) and thus can present with variable phenotypes (IIa, IIb, IV). Several phenotypes are present in the family members. This is in contrast to familial hypertriglyceridemia in which hypertriglyceridemia, but not hypercholesterolemia is present in family members (&, only It is likely that FCHL is due to an overproductfon of apolipoType IV). protein B (apo B) with or without overproduction of VLDL-TG.5,6 ANNUAL REPORTS IN MEDICINALCHEMISTRY-21

Copyright 0 1986 by Academic Prws, Inc. All rights of reproductionin any form reserved.

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Fredrickson Lipoprotein Phenotypes

Elevated Lipoprotein

Plasma Cholesterol

Plasma Triglyceride

I

Chylomicrons

Normal or Increased

Markedly Increased

IIa

Low density lipoproteins (LDL)

Increased

Normal

IIb

Very low density lipoproteins ( VLDL1

Increased

Increased

111

Abnormal

Increased

Increased

VLDL

Normal or Increased

Increased

Chylomicrons VLDL

Increased

Increased

B-VLDL IV V

Rare apolipoprotein disorders have been summarized.5-15 Type I11 hyperlipoproteinemia is characterized by hypertriglyceridemia, hypercholesterolemia, CHD and/or peripheral vascular disease, and is due in part to the presence of an abnormal VLDL (B-VLDL) caused by the inheritance of a gene coding for an abnormal form of apolipoprotein E (apo E-2). This apo E-2 does not bind normally to the LDL receptor or the chylomicron remnant receptor, preventing normal processing of both intestinal and hepatic lipoproteins, and resulting in the formation and accumulation of remnant lipoproteins or 0 -VLDL. However, only 1 in 50 individuals with apo E-2 develop the clinical symptoms noted above so other factor(s) must also play a role in the etiology of Type 111. For example, it is known that diets rich in fat and cholesterol cause the appearance of fl -VLDL-type particlesa7s8 and such diets may be even more atherogenic in apo E-2 subjects compared to normal individuals. Apo E, lipid transport and Type I11 hyperlipoproteinemia have recently been reviewed. 7-13

t

Various systemic diseases such as diabetes and hypothyroidism can produce conditions that resemble the primary hyperlipoproteinemias. l5 Other "secondary hyperlipidemias" are found in patients with liver or kidney disease, in obese individuals, or may be due to administration of drugs such as antihypertensive agents. Once the secondary hyperlipidemias have been ruled out by appropriate laboratory tests, the diagnosis of primary hyperlipoproteinemia can be made and dietary or pharmacologic intervention can be recommended. A new phenotype, hyperapobetalipoproteinemia, in which LDL concentrations are normal but the amount of apo B in LDL (LDL-apo B) is elevated,S is thought t o be associated with CHD and may be present with or without elevated TG. Recently, several forms of altered lipid transport termed "lipoprotein overproduction disorders," the underlying

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defect of which is excessive synthesis of apo B, have been described.16 By this criterion, hyperapobetalipoproteinemia occurs when overproduction of VLDL-apo B leads to increased conversion of VLDL to LDL (increased apo B/C ratio in LDL).6, l6-I7 Clearly, understanding more about the regulation of apo B synthesis could offer a therapeutic approach in the future for a variety of lipoprotein disorders.18,19 Pharmacologic Intervention - Lipid Regulators - In view of the generally accepted concept that LDL and HDL represent positive and negative risk factors, respectively, in atherogenesis, the term "lipid regulator" has to some extent replaced "hypolipidemic agent" for those drugs designed to treat lipid disorders. Emphasis on C distribution among lipoproteins is also evident with the use of various C ratios as atherogenic indices (e.g.HDL/total C, HDL/LDL, HDL/VLDL+LDL).Zo121 Dru s which only elevate HDL cholesterol are also under development.25 Based on the Framingham StudyYz3 the ideal therapy was thought to be one which would raise HDL as it lowered LDL. Recent published report^^^-^^ have suggested that the only question remaining is not whether but how to treat.33 Niacin, the oldest lipid regulator, is still recommended as the drug of choice for virtually all primary lipid d i ~ o r d e r s .The ~~~~~ discussion below concentrates on newer agents and includes only the most recent data for the established lipid regulators such as niacin. Bile Acid Sequestrants - Cholestyramine and colestipol are anion exchange resins which bind bile acids in the intestinal lumen. The therapeutic effects of this interruption of the enterohepatic circulation include upregulation of hepatic LDL receptors, lowering of plasma LDL and slight increases in HDL levels in Type I1 patient^.^^-^^ Althou h disadvantages of resin therapy are well d o c ~ m e n t e d , ~ in ~ ~recent ~,~~-~~ prospective, placebo-controlled, double-blind trials, cholestyramine significantly lowered the incidence and progression of CHD in hypercholesterolemic males.24-27 As a result of these studies, efforts to lower LDL and raise HDL appear to be worthwhile in terms of CHD risk. More dramatic lowering of LDL (50% reductions instead of 20% as for cholestyramine) has been advocated32 and may be possible with new resins possessing greater affinities for bile acids or with various combination treatments. Recently cholestyramine treatment has been reported to result in the accumulation of LDL with altered composition. Large, cholesteryl esterrich LDL particles are preferentially removed and smaller, more dense, cholesteryl ester-poor particles remain.44 Cholestyramine in combination with an agent which normalizes LDL composition, such as gemfibrozil, has been suggested.45 Inhibitors of Cholesterol Absorption - Agents which act in the intestinal lumen to block or slow the entry of C into the mucosal cells include neomycin,46 various surfactants-(AOMA or surformer,47 BEP 48 poloxalene 293049), plant sterols,50 steroids ( d i o ~ g e n i n , ~ ~ , ~ ~ sap on in^^^), sucrose polyester53 and synthetic glycosides. 54 Of these, neomycin lowered LDL as effectively as cholestyramine and may actually be preferred due to its lower cost and ease of admini~ t r a t i o n . ~Like ~ the resins, its primary mechanism of action is upregulation of hepatic LDL receptors resulting in enhanced clearance of both LDL and VLDL remnants and decreased LDL p r o d ~ c t i o n . ~ ~ Fatty acid amides are another group of compounds which inhibit C a b ~ o r p t i o n . ~Compound ~ 57-118 (1)lowered C absorption in rabbits by

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65%,58 and compound 58-035 (2)decreased C transport in lymph fistula rats.59 These acyl dmides, which are thought to inhibit C absorption by inhibition of intestinal C esterification by acyl-CoA:cholesterol acyltransferase (ACAT), are probably not systemically absorbed ,60 do not inhibit TG absorption59 or retinol esterification61 and, like 62 also inhibit the absorption of neomycinS6 and sucrose endogenous (biliary) C. !%lyester, Thus far, no clinical data are available for 1 or 2; clinical data for the earlier linoleamides r n o ~ t a m i d eand ~~ m e l i t ~ a m i d eshow ~ ~ decreases in serum C generally 5 10% in dyslipidemic subjects. Octimibate and CL-277,082 are ACAT inhibitors which appear to have direct anti-atherosclerotic effects on arteries of C-fed animals.

-

,

A C(CH ) --Sl-m 3 2 9

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1

I

CH -c 2 2

11

/“

0

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-2

-

HMG-CoA Reductase Inhibitors The mevalonate analogs compactin and mevinolin previously reviewed continue to be studied as agents for the ; ~ ~ ~isolation ~ ~ ~ ~ ~ ~ and ~~ treatment of h y p e r c h o l e . ~ t e r o l e m i a their actions were also, recently r e ~ i e w e d . ~ ~Recent , ~ ~ findings show that mevinolin does not deplete vital stores of body C,68 does not affect adrenal function69 and is eff icacious in even moderately hypercholesterolemic indi~iduals.7~ In a large, multicenter trial of mevinolin in FH heterozygotes, decreases in LDL-C of 42% were achieved.’l Compound 5 is another inhibitor of HMG-CoA reductase being developed which may possess advantages over other oxysterols since it is a precursor of C.39 It was recently shown to lower LDL (-46%) and elevate HDL (+57%) in rhesus monkeys.72 The HMG analogs 573and 774 have also been described.

Nicotinic Acid (Niacin) This lipid regulator has been-used since 1955 for virtually all types of d y ~ l i p i d e m i a s 35 ~ ~ ,des ite noncompliance due to side e f f e c t ~ . ~ 5 In the Coronary Drug Project 79 nicotinic acid reduced the incidence of nonfatal myocardial infarctions (MI), but the incidence of atrial fibrillation and other arrhythmias was increased. 39 Unlike HMG-CoA reductase inhibitors, C absorption inhibitors or bile acid sequestrants, nicotinic acid has no effect on the clearance of LDL by the liver. Its major action is to decrease hepatic VLDL synthesis by

Chap. 19 Drug Intervention in Athersclerotic Disease Newton, Krause

193

inhibition of adi ose tissue lipolysis and thus to limit fatty acid mobilization.76~7q Analogs of nicotinic acid are also in clinical use.39,77,78 Acipimox (8) elevated HDL in both Type IV and Type I1 subjects but did not lower total or LDL-C in Type I1 patients (IIa and IIb1.79 Other recently re orted analogs still in preclinical stages are glunicate (LG 13979,2)i0 and KCD-232

Probucol - Probucol modestly lowers total C and LDL-C by increasing LDL catabolism,82 primarily by nonreceptor mechanisms.83 It has no effect on TG and consistently lowers HDL-C by decreasing the synthesis of HDL apoproteins A I and A II.84 Probucol is lipophilic and alters the metabolism of lipoprotein^.^^ In monkeys fed high-fat diets, high blood levels of probucol were associated with cardiotoxicity.85 In some studies, no change in serum C or LDL-C levels with up to eight weeks of treatment was f o u r ~ d , but ~ ~ ,other ~ ~ reports showed that probucol caused re ression of xanthomas and lowered LDL-C levels in FH homozygotes.88-90 Chlorophenoxyacetic Acid Derivatives - Clofibrate and the other structurally related derivatives bezafibrate fenofibrate and may act by stimulation of LPL;yl TG lowering is the ciprofibrate A Rn major pharmacologic effect. All of these drugs have been 8, c1 CH CH r 3 3 reported to elevate HDL. ~R2 o c -C- - o -Q-A b, ClGCONH(CH,)2 H However, in direct comparative studies both Ug2 and I CH c, C l e m ( c H ~ =g3 ) ~ elevated HDL to a 3 11 greater extent than & in Type d, Cl*C--c /? H I1 patients. In hypertriglyceridemic subjects, elevated only HDL3 94 while elevated only HDL without accompanying changes in apo A I or A I1 metabolism.?5 Bezafibrate is the only derivative shown to increase receptor-mediated clearance of LDL in hypercholesterolemic individuals.g6 Fenofibrate increases the fractional catabolic rate of LDL-apo B in heterozygous FH subjects which is also consistent with enhanced receptor activity.97 Eisenbergg8 has postulated that hypertriglyceridemia alters the composition and hence metabolism of all lipoproteins, thus contributing to atherogenesis. For example, LDL from hypertriglyceridemic subjects is less effective than normal LDL in interacting with the LDL receptor, and this defect is reversed by bezafibrate therapy. 99

(u)

(m)

Gemfibrozil - Gemfibrozil (12)is often considered separately from clofibrate and its congeners in view of its structural differences. In contrast to and , 12 elevated HDL-C and lowered liver C concentrations in C-fed rats.loO Gemfibrozil also prevented decreases of apo E in C-fed rats, O1 a property not shared by lla-d.lo2 In hypertriglyceridemic subjects, but CH 3 not =g5 CH3 increased the synthesis (and plasma concentration) of apo A1 and A11 without 12

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and Endocrine Function

Pawson, Ed.

changing the catabolism of these HDL peptides. Unlike 12 decreased LDL-apoB production in hypertriglyceridemic patientsFo4 although both drugs tended to normalize LDL c o m p o s i t i ~ n . 12 ~ ~also ~~~~ decreased the rate of VLDL-apo B and intermediate density lipoprotein (IDLl-apo B synthesis in Type I11 subjects.lU5 In a direct comparison in hypertriglyceridemic individuals, 12 both decreased the production and only affected increased the clearance of VLDL-TG whereas clearance.lo6 The ongoing 5-year Helsinki Heart Study is designed to test whether all of these lipid-regulating effects will prevent CHD in (primarily) Type I1 male subjects. Pantethine - Pantethine (G),a pantothenic acid derivative presently marketed in Japan for dyslipidemia, lowered C and TG concentrations and elevated HDL in Type IIb subjects.lO8 Stimulation of LPL in rats109 and elevation of HDL in rabbitall0 have been reported, consistent with the clinical findings. In a recent report, 2 was shown to Y inhibit the in vitro peroxidation of LDL.

-

Combination Therapy The clinical use of two lipid regulators in combination has provided superior efficacy for the treatment of severe hypercholesterolemia. In a recent study, efficacy (LDL lowering) with the combination of probucol (lg/day) and colesti 01 (10g/day) was as great as with the full dose of resin (20g/day), lP2 and without the gastrointestinal side effects associated with resin treatment. However, the resin did not prevent the decrease in HDL induced by probucol. The combination of neomycin and nicotinic acid decreased LDL-C more than with neomycin alone.55 Compactin114 and mevinolin115 were shown to enhance the LDL-lowering due to resin thera rimarily by increasing the fractional clearance rate of LDL. lPS: lP6 Such combinations produce reductions of LDL similar to those reported with colestipol plus nicotinic acid (50-55%1117 although the mechanism for the latter is not as evident.39 Antihypertensive Drugs and Dyslipidemias - Certain classes of antihypertensive drugs have been found to affect TG and C metabolism and result in an undesirable plasma lipoprotein profile. Since antihypertensive therapy is long-term and such changes in lipoprotein metabolism may promote the atherogenic process, the situation arises whether high blood pressure is being controlled at the expense of increasing the effect of other major risk factors, hypercholesterolemia and/or hypertriglyceridemia. It is interesting that although antihypertensive drugs have been effective at decreasing mortality due to stroke and congestive heart failure, they have been relatively ineffective at protecting against CHD and MI. 118 Loop diuretics, potassium savers, thiazides, and related drugs have been shown to increase both total plasma TG and VLDL-TG values in studies ranging from three weeks to one year in duration. 1193 120 In addition, serum C levels are increased (5-10%> with diuretics, the effect due predominantly to increases in LDL-C (4-20%) while HDL-C is relatively unaffected. 121, 122 In contrast, peripheral and central sympathetic blocking agents such as reserpine and methyldopa depressed HDL-C levels, but did not adversely affect TG concentrations.123

Chap. 19 Drug Intervention in Athersclerotic Disease Newton, Krause

195

Of the 6-blockers, propanolol has been the most widely evaluated for effects on lipoprotein metabolism. 122-126 More dramatic increases in VLDL-TG levels were observed with both selective and nonselective @-blockers than those possessing intrinsic sympathomimetic activity (ISA). However, some studies showed a significant reduction (15%) in HDL-C levels without affecting total C and LDL-C values.124,125 An added problem with ropanolol is the propensity for elevated uric acid and glucose levels. p25 Thiazide diuretics can cause hyperglycemia and inhibition of LPL due to peripheral insulin resistance and CAMPstimulated lipolysis in adipose tissue, which increases both hepatic and extrahepatic originated substrate for TG synthesis.120 In contrast, 6-blockers inhibit adenyl cyclase activity in adipose tissue leading to reduced hormone-sensitive lipase activity and decreased mobilization of fatty acids. 123 Recent evidence indicates that the plasma half-life of an intravenous TG emulsion is increased with 6 -blockers without ISA.126 However, long-term studies with labetolol, an a - and f3 -adrenoceptor blocking drug, lasma lipoproteins and their metabolism showed no adverse effects.O?25 In contrast to the effects of both thiazide diuretics and the B-blockers, the postsynaptic selective al-antagonist prazosin has not only been shown to be an effective antihypertensive agent, but also to produce a healthier lipoprotein profile. In both man and animals, prazosin reduced circulating plasma TG and VLDL-TG levels. 123-1269 128 In chow-fed rats and rats fed a high glucose diet prazosin lowered plasma TG concentrations by 40-50% with the change being secondary to a fall in VLDL-TG secretion rate.128 In studies of the effects of prazosin on human plasma and lipoprotein-lipid indices, beneficial alterations in HDL-C, LDL-C, and VLDL-C and total TG values were achieved. In addition, prazosin in combination with certain diuretics or 6 -blockers reversed the undesirable effects of these two classes of antihypertensive agents on plasma TG and VLDL-TG levels, and to a lesser extent on HDL-C and LDL-C.129-131 Another a -antagonist, urapidil, was neutral in terms of lipid responses.133 Two other classes of antihypertensive agents, vasodilators and ACE inhibitors, have also been evaluated for effects on lipoprotein metabolism. The vasodilator carprazidil (RO 12-4713) consistently increased HDL-C without affecting other lipid and lipoprotein parameters during 4 months of therapy.132 The ACE inhibitor captopril produced no consistent adverse alteration in plasma C and TG levels in both shortand long-term clinical trials. 134

Importance of Calcium in Atherosclerosis - There is increasing evidence that ionic calcium (Ca*) may play an important role in the pathogenesis of atherosclerosis. Under normal conditions, the influx of Ca* into cardiovascular cells appears to serve as a "second messenger'' and its binding to calmodulin intrace1lularly mediates numerous Ca*-dependent functions, &, contraction-relaxation in contractile cells, chemotaxis, stimulus for mitosis, various platelet functions, secretion of connective tissue components, endocytosis of LDL and cellular energy production. However, the fatty streaks appearing in childhood, which contain calcified vesicles from degenerated cells of the intima and media, have provided evidence for the early onset of abnormal Ca* metabolism.135 Further analysis of these necrotic regions indicated a diffraction pattern similar to apatite and Ca* bound to selected proteins. In late-stage plaque development, mineralization of connective tissue and cell debris have also been reported. In addition, elastinolysis and necrosis have

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Diseases and Endocrine Function

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resulted from intracellular Ca* accumulation causing cell death and release of lytic en~ymes.l3~, 137 Extracellular Ca* has been shown to mediate macrophage elastase activity, increase binding of lipoproteins to connective tissue proteins, and promote calcification of surrounding soft tissue. U8-141 Alteration in membrane lipid composition has also augmented Ca* entry and has had deleterious effects on arterial cell function. 1421 143 Constrictor effects in isolated canine coronary arteries by a high C environment were blocked by calcium a n t a g 0 n i ~ t s . l ~ ~ Thus, these studies support the regulation of Ca* entry into arterial cells as an approach toward beneficially affecting the atherosclerotic process. Anti-Atherosclerotic Effects of Chelating Agents and Calcium Entry Blockers Subcutaneous injections of the chelating agent magnesium ethylenediamine-tetracetic acid (EDTA) to C-fed rabbits exerted an anti-atherosclerotic effect by significantly reducing arterial elastin and collagen. 144 Recently, several other calcium chelating agents were tested in both New Zealand white rabbits and in monkeys (Macaca fascicularis) fed atherogenic diets.l4l The drugs used in these studies included ethane-1-hydroxy-1,l-diphosphonic acid (EHDP), azacycloheptane-2,2-diphosphonic acid (AHDP), 2-iminopyrrolidone-5,5diphosphonic acid (IPDP), amino-1-hydroxy-propane-l,1 diphosphonic acid (APDP), lanthanum (LaC13), an inhibitor of calcium uptake via receptor channels and trimazosin, a CAMP phosphodiesterase inhibitor. Although not one of these compounds showed significant plasma lipid-regulating activity, all suppressed aortic accumulations of calcium, phosphorus, collagen and elastin, and reduced aortic accumulation of C and minimized foam cell formation and intimal thickening. More recent reports have confirmed the anti-atherosclerotic effect of EHDP in swine and extended the observations in rabbits to include a reduction in the amount of necrosis in early lesions. 145,146

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Since calcium entry blockers inhibit calcium influx without causing bone demineralization, nifedi ine (14) has been studied in rabbits with diet-induced ather08clerosis.~47 Although changes in plasma lipids did not occur, significant reductions in sudanophilic lesions, aortic C content and aortic calcium were found compared to untreated controls. Similar results for both nifedipine and nicardipine (both at 40 mg/kg bid) were recently r e ~ 0 r t e d . l ~Low ~ dose nifedipine (2 mglday) was also effective in rabbits. 149 In Watanabe heritable hyperlipidemic (WHHL) rabbits, which lack the LDL receptor, nifedipine (40 mg/day over 26 weeks) showed no obvious difference in plaques covering either the aortic arch or the thoracic aorta when compared to an untreated group.150 In another study, nifedipine (20 mg bid) was given to Japanese white rabbits fed a 2% cholesterol diet for 12 weeks compared to WHHL rabbits fed chow for 20 weeks. Atherosclerosis was suppressed in the Japanese rabbits but not in WHHL rabbits.151 Other investigators have also failed to demonstrate an anti-atherosclerotic effect of nifedipine in C-fed r a b b i t ~ . l 5153 ~ ~ In rhesus monkeys treated with nifedipine over 12 months and fed an atherogenic diet no significant effect on any aspect of atherosclerosis was observed.i54 Verapamil ( 2 1 , a slow channel calcium antagonist, showed protective effects on atheroslerosis in C-fed rabbits,155 but not in WHHL rabbits. In a recent study using verapamil and a lipid-lowering diet in rabbits with aortic atherosclerosis, the combination halted further rogression of the disease in those rabbits previously fed a C-diet. lJ7 Diltiazem, propanolol, reserpine, guanethidine and

Chap, 19 Drug Intervention in Athersclerotic Disease Newton, Krause

197

flunarieine are other compounds affecting arterial calcium deposition which have been reported to beneficially affect the atherosclerotic process. 158,159

(14) The mechanism of action of the chelating agents and calcium entry blockers at the cellular level is not well understood, but may be due to effects on smooth muscle cell migration, mitosis,141 inhibition of collagen synthesis and secretion,160 and/or a specific effect on cellular lipoprotein receptor activity. Similar mechanisms have been reported with diphosphonates 164 Other proposed mechanisms include increased lysosomal and cytoplasmic cholesteryl ester hydrolase activity165 and inhibition of ACAT activity via suppression of sterol carrier protein, both of which would reduce cellular C accumulation.

.

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Future Approaches The complexity of communication between cells of the arterial wall and the disrupting effects caused by blood-borne cells (macrophages, platelets, neutrophils, etc.) interacting with them make the discovery of effective anti-atherosclerotic drugs a difficult task. Since cholesteryl ester accumulation in the atherosclerotic lesion is the hallmark of the disease, plasma lipid regulators have been given the most attention. Although substantiation of the LDL-C and HDL-C hypothesis is a step forward, minimal information presently exists about cellular events and interactions which are pro- or anti-atherosclerotic. As a better understanding of cellular processes and intercellular communications in the arterial wall is realized, more specialized therapy will become available. Some new approaches include anti- roliferative and anti-angiogenic effects of heparin-like molecules,16q-170selective and nonselective inhibition of thromboxane and/or stimulation of prostacyclin for ma ti or^,^^^-^^^ re ulation of specific cyclic nucleotides and phosphodiesterases,195-178 and modulation of the release of cell secretory products affecting lipoprotein uptake. 179-182 Although these areas of investigation hold great promise, it is likely that no single form of therapy will prove efficacious for all patients at risk for premature CHD. References 1. J.D. Rugh, C.S. b n e y and R.L. Sldth, h u . Rep. kd. b., &, 161 (1983). 2. M.S. Brown and J.L. Goldstein, ki. h . ,251, 58 (1'3%). 3. S.M. Gnmdy, Cardiowsc. M., 39 (1%). 4. G. Asslarn, ''Lipid k&kolisnand A t l w m s c l m m b , " F.K. schattawr Verlag. Stut-, 15182. p. 115. , J.J. Albers and P.O. Kwiterovich, Arteriodercas ' , & E l ( 1984). 5. J.D. E!nmzdl. A.D. 6. S.M. Gnmdy, G.L. Vega and Y.A. Kesanierri, kta M, %and., 701, 23 (1%). -7. R.W. W e y , Circulation,2 W (1%). 8. R.W. W y and T.L. I n w a r i t y , Bicchim. Eiophys. kta, 737,197 (1983). 9. V.I. ZanniS and J.L. Breslov, bl. @u. E i d l m ~ . , g,3 (1%2). 10. R.W. W y . M. Clin. N. Am., g,375 (1982). 11. R.W. M k y . Klin. kckmzhr., 225 (1983). 12. G. uterrrwn. I. ISdenmm, H. Kaffarnik and A. Steirmtz. Hun. Met.. 6 5 - 232 (I*). 13. R. W. k h l e y , T.L. Innerarity, S.C. R s l l and K.H. Weisgraber, J. Lipid Res., 3 1277 (1984). 14. J.L. Breslow, HDSP. Ract., 2,43 (1485). 15. R.J. Havel, M. CLin. N. h . ,& 319 (1982). 16. S.M. M y , J. Lipid Res., 3,1611 (1'3%). 663 (1986). 17. B. Teng. A.D. snidenw , A.K. Soutar and G.R. lmpsm, J. W. Invest., 18. B.R. KrarrsedR.S.Newtcn.'IL-endsRrlrm. =.,% 384(1984). 19. B.R. Krause. Ikug Dwelop. Res.. 4 155 (1985). 20. M.S. Green, G. kiss, B.M. Rifkind, G.R. Cooper, O.D. Willirns and H.A. Tyroler, circulation, 2, 93 (1985).

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- Metabolic Diseases and Endocrine Function

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and A.M. I(0Ss. Am. J. Cardiol., 21. S.B. Schnidt. A.G. khsenmn, R.A. k j n g , S.E. schlesselman,J.C. 55, 1459 (1585). 22. R. Fears, A. M l , P. walker, W.R. Rush and H. Ferres, Biochen. pharm., 3,219 (1%). 23. W.B. Kannel, W.P. Castelli and T. G0rdm-1, AM. Jnt. M.,g,85 (1979). 24. Lipid Researd! Clinics hogran, J. h. W. k .251, , 351 (1%). 25. Lipid Research Qinics Rogm, J. h. W. pssoC., 251, 365 (1%). 26. J.F. Brensike, R.I. Levy, S.F. Kelsey, E.R. Passarraru', J.M. Ricbrdson, I.K. Loh, N.J. Stone, R.F. Aldrich, J.W. Battaglini, D.J. b r i a r t y , M.R. Fisher, L. Friedmn, W. Friedewald, K.M. ktre and S.E. Epstein, k u l a t i c n , &, 313 (1%). J.W. Eettaglini, D.J. b r i a r t y , M.L. Fisher, 27. R.I. Levy, J.F. Richardson, I.K. I&, N.J. Stone, R.F. Al-, L. Fx-i~dum,W. Friededd and K.M. ktre, C i r c ~ t i o n 3, . 325 (1%). Blood Qlolesterol to Prevmt Disease. J. h. on 28. Canrenas DweloolEnt Panel. carensllsCcmfer-

29. 3. W.P. KaMel, J.T. Doyle, A.M. Cstfeld, C.D. Jenkins, L. K u l l e r , R.N. podell and J. Stanler, Circulation, 3, 157A (1%). S.M. k d y , J.A. Little, 31. A.M. Gotto, E.L. BLernan, W.E. Connor, C.H. Ford, I.D. Frantz, C.J. Qd, circulaticn, 1 m (1%). 32. S.M. Gnmdy, A.M. Cotto, W.C. Roberts, H.K. Naito, J.E. O'Brien, B.M. Muhknus, J.C. LaRasa, B.M. Rifkind andG.R. Cooper, Pm. J. (ludiol.. U (1935). 33. R.I. Levy, Circulation, 3 6% (1%). 36. E.J. schaefer in 'Type 111Hyperlipopmt&mia: Itiagrosis. blexlzu- Defpts. Etlthology and Treabnac,': Ann. Int. W., (part l), 623 (1983). 35. J.M. keg, R.E. Segg and H.B. Breer, J. Am. W. Assoc., 255, 512 (1%). 36. C.J. Fhckird and J. shepherd, J. Lipid RPS., 1C61 (1'232). 37. J. S q h e r d , C.J. Fkkard, H.G. brgan, J.L.H.C. l h i r d , J.M. Stewart and T.D.V. M e , Atherosclerosis, 3 433 (1979). 38. W.V. km, I.J. Goldberg and H.N. Ginsberg, Prop. cardiow. Dis., 2z, 1 (1%). 39. R. Fears, Drugs of Today, g,257 (1%). 40. M.N. Cayen, D r u g k t . Rev., 11,291 (193.3). 41. J.C. IaRosa. Angiology 33 562 ( l m ) . 42. D.B. hnin$&e, Rev. Rep., 2,1184 (1W). 43. E.J. %hadm and R.I. Levy, New Ehgl. J. M., 312. 1333 (1935). 44. J.L. Witztun, S.G. Yomrg, R.L. Elam, T.E. &re++and M. Fisher, J. Lipid k., g,92 (1%). 45. G.L. Vega and S.M. M y , J. h. Med. kssoc., 253, 2348 (1%). 46. A. sedaghat, P. SBRlel, J.R. C r o w and E.H. k e n s , J. Clin. Invest., 3 12 (1975). 47. J.R. Crouse, S.M. M y and J.H. hhnsm, ktablisn, 3 l , 733 ( 1 s ) . 48. B. K ,a W.J. Bochenek and K. F'ikledcz, Atherder&, 5 235 (1%). 49. J.B. Rogers, E.C. Kyrialades, B. KapisciFske, S.K. Pmg and W.J. Bochenek, J. Clin. Invest., & 1440 (1463). 50. G.V. Vahnmy, W.E. Conner, S. Subrammian, D.S. Lin and L.L. W o , h. J. Clin. Nutr. 3 835 (1983). 51. J.C. Diaz Wy3, J. Lagtlna and J. Gmm-Gmm ' , Biochen. R.mm., 3 2473 (1971). 52. M.R. Mirum, P. kLa+, C. Sta€ford. A.L. L.i~@~rn, G.O. Kdh- and P.R. oleeke. Am. J. Qin. Nutr., 1810 (1979). F.H. Egttscn and R.J. Jandacek, h. J. Qin. Nw.,3 1636 (1979). 53. C.J. Qd, 54. M.R. Minrm, P. k L a w , B. Upscn, J.O. Gardw and J.T. k h ,Arte!i~lerosis, 3 5% (1%). 55. J.M. keg, M.B. b k ~ E., BOU, L.A. zech, K.R. Bailey, R.E. G q g , D.L. Sprecher, J.K. Susser, A.M. pikus and H.B. Brewer, circulatim, 1034 (1%). 41 (1%). 56. Y.A. I h m i d and S.M. Grundy, Artericsclerosis, 16 (1977). 57. D. Kritcbvaky, S.A. Tepper and J.A. Story, Lipids, 58. J.G. kider, C.E. Pickens and L.A. Kelly, J. Lipid Res., 24, 1127 (1983). 59. S.B. Clark and A.M. Tercyak, J. Lipid Res., 3 148 (1984). H. kkatani and K. T d d , xenobiotica, 5, 329 (1976). 60. A. H i d w d u', A. kgata. H. Mi-, K.J. Go, J.G. Mder and G.H. b t h b l a t , J. Biol. h.259, , 815 (1%). 61. A.C. k. 62. F.H. kttstn ind R.J. ,lindacek, Lipids, 9 273 (1%). Qin. pharm. b p . , &, 368 (1975). 63. N. Takeudd a d Y..-Y 64. Double BLind Study Group. k l j n m i d e , Qin. E d . , 2, 355 (1'231). 65. G. sdnritz, R. Nienann, B. F3rermh%wm,R. Krause and G. Asamnn, EM83 J., 5, 2773 (1%). 6. V.G. kvries, S.A. schaffer, E.E. targis, M . D . h t i a , C. bbg, J.D. Blmnand A.S. Katws, J. W. b., in press. 67. A. Endo, Adv. Exp. W. Biol., 183,295 (1%). PIX. ktl. prad. Sci., 2538 (I%), 63. S.M. M y and D.W. n, 69. D.R. Illingk0rt.h and D. brbin, Roc. &tl. prad. Sci.. g,6291 (1%). 70. S.M. Gnmdy and G.L. Vega. J. Lipid Res., 1464 (1%). 71. R.J. M.D.B. € b n b g b k, D.R. Iuinguorth. R.S. Lees. E.A. Stein, J.A. Tobert. S.R. BBUXI, P.H. Frost. G.E. Laddn, A.M. Lees and A.S. Lecn. Arterimlemds. 2. 512a (1585). 72 G.J. sdwepfer, B.C. 9will, K.S. khg, W.K. Wilson, A. Kisic and T.B. clarkson,Prcc. Natl. prad. Sci., & 6861 (1984). 73. J.S. Buan, I. Laos, D.D. tangford, J.E. Hiller, C. Jeff, B. Taite and E. Rohrbacher, J. Med. Um., g, 597 (1%). , 1 (1%). 74. T.G. Nguyen, K. Gerbing and H. Fggerer, I b p p e S e y l e r ' s 2. physiol. h.365, Group, J. h. M. Assoc., 231, 360 (1975). 75. Coronary Drug Rojezt -ch 76. R.J. Havel, Cardiow. Rev. Rep.. 2,1163 (1982).

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I

Chap. 19 Drug Intervention in Athersclerotio Disease Newton, Krause

n.

2

W. ktz. Adv. Lipid Res 20 195 (1983). &uu C.R. Sirtori, Am. J. Cardiol.. 2lB (1983). 78. R. Faoletti, G. F ~ w c e"'-and 79. D. Snmriva, I. Pugliaghi, D. M i g l i o l i , C. Chbrini, M. T i r r i t o and M. Lavepari, Current Therap. Res.,

x,

7 3 363 (1%). M. CriscwJi, A.R. F?mzetti and A. Subissi, Afh?rascler&, 3 59 (l%). 81. T. Irikura,K. Takagi, K. acada and K. Yagasala, Lipids, 2J, 420 (1985). a. Y.A. Kasanienri and S.M. M y , J. Lipid Res., 2,78) (1%). i un and D. Steinberg, J. Lipid Res., 2, 1206 (1%). 03. M. Namsma'cz,T.E. Carew, R.C. Pithmn, J.L. Wm and J. S h e w d , J. Lipid Res., 2,588 84. R.F. A M , J.M. Ste*art, D.E. Boag, C.J. Packard, A.R. Lo8).

(1983). ,\ - - -

85. 86. 87. 88.

89. 40. 91. 92. 93.

94. 95. %. 97. 93.

99. 103. 101. 102. 103. 104. 105.

H.A. Eder, Artery, 3 105 (1982). D.R. Lnk, I. Kuisk, B, Gonan, W. Pa& and G. Schcnfeld, A t h e r d e r m i s , 42, 271 (1983). P.J. k t e l and T. l&llington, At.h%osclerasis, 2, 203 (19881). J. HeMhan, J. Am. M. Assac., 246, 2 3 3 (19881). R.S. kinis, H.R. e r e , L.A. kicker, I.M. Kimand E. Rubin, J. Am. Wt. Sa., 2, 167 (1974). A. Yanenoto, Y. htsuzava, B. K i m ,R. I t a m ,K. H i r o k and T. K i k h a , Atherosclerasis, g, 157 (1983). C.R. Sirtori, Adv. Exp. M. Biol., 183,241 (1985). J. Rwffy, B. chanu, R. W, F, Djian and J.G. Lceper, Atherosclerosis, 2,273 (1585). P.A. Tesone, J. Gladstein and A.M. Aana, h. M. Res. @in., 3 6% (1985). J. Sqkrd, M.J. caslake, A.R. Lorimer, B.D. V a l l a o c e and C.J. Fackard, Arteriderc6is. 1 .162 (1%). J. Skepkrd, C.J. Packad, J.M. Stmart, R.F. A t m h , R.S. (Ilark, D.E. bag, K. Carr. A. R. lo-, D. Ballantyne, H.G. br&rpland T.D.V. Iaurie,J. Clin. Invest., 3 2164 (1984). J.M. Stecrart, C.J. W,A.R. h i m r , D.E. b a n d J. Sqkrd, Atherosclerosis, 3, 355 (1932). C.L. Pkhrtdier and C. Iklcroix, A t h e m s r l e r o s's, l 161 (1%). s. Eisenberg, Adv. !3p. w. Biol., 183,73 (1985). Y. Kleinren, S. Fdsmberg, Y. k h y , D. Gavish, 0. Stein and Y. Stein, J. Clin. Invgt., E, 17% (1%). R.E. k l l , J.W. Nawmki and P.D. Llhlendorf, Atherosclerosis, 195 (1483). B.R. Kraw and R.S. NRJton, J. Lipid Res., 26, W (1985). B.R. Kram and R.S. Newton, A t h e r d e r & , 3,95 (1%). 1702 (1%). K. W u , P.S. h i d e , B.A. Hynd and M.L. W y a p , J. Win. Invest., G.L. Vega and S.M. Gnn-dy, J. Am. M, Assx., 2y, 2398 (1%). P.R. Tuner, C. costese, R. bm, C. Marenah, N.E. Etiller and B. Lewis, b p . J. Win. Invest., 5 lCD

x,

g,

(1%). ' and S.M. M y , J. h.M ,Asscc., 251, 2241 (1984). 18. Y.A. Kasmmm ' 107. v. t,hmiMl, kta M, scand. (Suppl.), 701,03 (1%). L. Colonbo, A. Craveri, G. h t m a r i and C.R. Sirtori, 103. A. Gaddi, G.C. Descovich, G. Noseda, C. Fm-, Atkr~lerosis, 73 (1%). 109. A. Nara, M. Kita and T. W y a , brm. kt. Res., &, 233 (1%). 110. P. can;lra, L. bktturi, M. Galbusjera, M.R. LDvati, G. F r a n c ~' h'mand C.R. Sirtori, A t h e m d m i s , 3 255 (1%). 93 (1985). 111. G.B. b,G. cauolato, S. zag0 and P. A v c g a r o , A t h e r a s c l e r o s i s . 112. C.A. h-, S.B. Ummff, P. Krehhiel. B. -ladcson, S. M h r s e y and H. Taylor, Am. J. Grdi~l., 1514 (1984). 113. J.M. .!a%mn and H.A. Lee, A t h e r o s c l e r ~ 2 , 189 (1984). 114. H . M ~ w h i , T . S a k a i , Y.Sakai,A.Yashinnna, A.btanabe,T.Waka~u& J. KoizmiandR.Takeda,NewFngl. J. k d 308 609 (1983). S.M. M y , M.S. Brown and J.L. Goldstein, Ra. ktl. A d . Sci., g,4124 (1983). 115. D.W. E&&-, 116. S.M. Gnmdy, G.L. Vega and D.W. Bilheimr, Ann. ht. M., 103,339 (1%). 117. J.P. Kane, M.J. W o y , P. k, N.R. Phillips, D.D. Freeran, M.L. William, J.S. Rw and R.J. k v e l , New Fngl. J. M., & 251 (1981). 118. M.H. Wberger, Pmr. J. W., g,(Suppl. a),64 (1%). 5121 (1985). 119. J.D. Spence, J. Cardiovasc. k., 120. R.P. k, Am. J. Cardiol.,Sl, 632 (1983). 121. C.J. G l d , Am. Heart J., 9, 1107 (1985). 122. P. Weichm, A. h k e n and R. brdasini, Hypertension (Suppl. III), 5, III-120 (1%). 123. B.F. Johnscn, J. Cardiovasc. Fhmn., i,S213 (1982). 124. R. Cutler, Am. J. Cardiol., 2, 628 (1983). 125. P. van Ennmln, J. Cardio~sc.Fhmn.,2,551 (1ss3). Sci., 3, 713 (1%). 126. P.N. brkgton, W.C. Brodee and D.M. Large, 127. B. Hglander, K. ELiasscrr, P. Nilsson-Fhle and S. Rocsler, kta M. Scand., 218, 51 (1%). 128. GM. Ream and E. W'Aglio, J. cardiovasc. pharm., 4 (Suppl. 2), 5248 (1982). 129. A. Zamh?tti, kn. J. M., E, (24). 122 (1984). 13. J. huffy and J. Jaillard, Pm. J. M.. 2 (24). 105 (1%). E(24),67 (1%). 131. P. Leren. kn. J. M., 132. A. Gerber. P. W&kmnn. B. Saver. M. Bianchotti. R. Zinden. L. Link, W. Riesen and R. brdasini. k t a b . .

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133.

134. 135. 136. 137. 138. 139.

J.T. W, S.S. Tadros, G.R. D r z m i l k i and A.C. Jenkins, Hypertensim, 2, (Suppl. =I), 111-145 (1983). A. Tanimna, D.H. McGregor and H.C. Anderson, Prcc. SOC. Ekp. Biol. Wed., 173 (1983). 479 (1979). M. Yola~yamand P.D. Hwry, Circ. Res., R. Ross, Arterroscl . ercsis, 293 (1981). P.D. Henry, Cbculaticn, 4% (1%). F.V. &?Feudis, Life Sd., 3, 557 (1%).

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Section I V

- Metabolic Diseases and Endocrine Function

Pawson, Ed.

140. W.W. M e y , S. BlunLein and R. sievers. kn. J. cardiol.. 3 16% (1%). 141. D.M. Krarsch in "Cqs Altering Lipid W U , "D. Kritchevsky,.W.L. b h and R. paoletti. Eds.. Plenm Ress, NEW York, N.Y., 1985, p. 323. 24, 822 (1%). 142. R. Iocher, L. Neyses, M. Stimpel, 8. Kueffer and W. Vetter, Biochm. BioFhys. Res. h,1, 143. L. Neyscs, R. kcher, M. Stjmpel, R. S t w l i and W. Vetter, B i d . J., 2T7, 105 (1%). 144. A. Wartnan, T.L. Imp?, D.S. McaM and A.J. Ebyle, J. Athem. Res., L 331 (1967). 145. AS. M,AS. Frank and J. Jarolych, Arteriosclerasis,I,52% (1%). 146. AS. Frank, W.T. Ram and A S . Dmd, Arteridercsis, I, 527a (1%). 147. P.D. Henry and K.L. kntley, J. Qin. Invest., &, 1% (1981). ' , M.A. whyte, D.L. Smith, I. M m d and D. Puppicne, A r t e r i d e r m i s , 148. A.L. Willis, 8. kgel, V. owdull

5

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149. S. Bnagiotoph and W.G. Naylor, J. bl. W. k d i o l . , &, XTV (1%). 150. J.L.M. VanNkkk, T. Hmdriks, H.H.M. Boer and A. Van't Iaar, Atheroderosis, 3 91 (1584). 151. N. watanabe, Y. Ishikaka, J. bk&t& N. M w i ,M. Tfllkitani, S. Takano, R. C ~ U ~ O Y., ktanabe and H. Fukluzald, Arteriosclerosis, 1 . 5 7 3 (1%). 152. I. .-S B. Nordestgami and K. Kjeldsm, Artericsclerosis,4 389 (1%). 153. M. Naito, F. Kuplya. K. A&, K. ShihtaradN. Yoshindne, Angiology, -5 3 622 (1%). 154. H.R. m h , J.F. u, T. ~ h mD., v-~mh and R.W. w,~rteriosrleross . ,J 52h (1985). 155. s. m m , R. s i . ? ~P. ~ ~, i d md d W.W. parmley, kn. J. cardiol.. 3 884 (1%). 1%. G.D. Tiltm, LA. Buja, D.W. Bilhejloer, P. Apprill, J. Ashtcn. J. H t t . T. Kita and J.T. Wjll-, J. kn. (loll. ctadiol., 4 141 (1985). 157. R. sievers, T. W d , J. Garrett. S. Blunlein ad W. filrmley. Arteriosclemsis, 5. 53Qi (1%). -ti and 0.Qrrier, Athemsclemsls . , 337 (1973). 158. P.J. M 159. P.J. khitthgh-dblemn and 0.Carrier. Atherosclemsis. 3 15 (1970). 160. L. FlaMLzi, E, Lam, A.D. Ram, G. Pssogra, D. GoggiandG. Ricevuti, DrVgsExptl. CLin., XI, 845 (1%). 161, S. Panganattm and R.L. Jackson, Biochen. hum., 22, 2377 (1%). 162. S. kingamthan, J.A,K. tLumny and R.L. .kkm, Biochm. Biophp. Res. Carrmn., _107, 217 (1482). 163. 0. Stein, E. LeitersdDrf and Y. Stein, Artericrsclerosis, 3 35 (1985). 164. C. Minbn, L. Radadjia and P. Golhter, Wcif. Tissue Res., $ 161 (1974). ,165. O.R. Etingin and D.P. Hajjar, J. Qin. Invest., 1554 (1%). 166. B.A. bttke, M.C. Alley, L.K. Bale, D.M. Dink, C.D. Olson and M.E. Danpsey, Arteriosclerosis,& 42% (1%). 167, H. Ehgelberg, h. Re-, & 91 (1584). 168. J. F o h . Eioctm. M.,2,905 (1985). 169. M.J. Kamovsky, J.J. Castellot, Jr., G.M. b t a and R.D. Rosenberg in ''InteractiCnS of Platelets w i t h the V e s s e l W,"J.A. Oates, J. Hawiger and R. ROBS, Eds., h i c a n Fhysiolcgical Society, Eethesda, MD., 1%, p. 147. 170. D.A. kndley, Drug Developlpnt k.. 4 167 (1%). 171. S. b d a , ArterioscleKsl 's, 2,193 (1W). , Fkm~l. 35 633 (1%). 172. G.A. fitzgerdd and J.A. b t e ~ Qin. n % t~ e r x t i a ~ ~ of platelets w i t h the V d W," 173. G.A. Fitzgedd, D.M. Fisher, J. tbtan and J.A. b t i ~ J.A. Oam, J, HawigerandR. Ross. Fds., k m i c a n F h y s M @ A S a c i e t y , Bethesda.MD.. 1985, p. la. 174. S.R. Harwm, L.A. k k e r and T.D. B m , J. Clin. Invest., 5 1591 (1985). 175. M. -V and R.J. K a s h , J. Qin. Invest., 5 233 (1%). 176. A. F?eretz. F. Brhm&&a 'd. A. Stierle. G. Come. R. Antonand J.4. W v e , Biochw. h. 3, 257 (1%). in. T. Kariya, F. brito, T. Sakai, K. Takahata and M. Y d , Arch. h. 331, , 119 (1985). 178. H. Hidaka and T. hdo, Adv. Cyclic W m . R o t . Rospho. k., 145 (1%). 179. D.R. W p s , K. Arnold and T.L. Irmeraity, Nature, 316. 746 (1985). 180. M.K. C a w , P.W. k e l and G.M. olisolm, J. Leukocyte Biol., 361 (19aS). 181. T. Hmrikn, E.M. Matcney and D. Steinberg, Arteridercxis, 2, 149 (1%). ' lerffiis, 5 134 (1482). 182. A. ( h i t and T. kmxe, art en^^

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Chapter 20. Therapeutic Approaches t o Rheumatoid Arthritis and Other Autoimmune Diseases Michael C. Venuti Institute of Bio-Organic Chemistry Syntex Research, Palo Alto, CA 94304 Introduction - The management of autoimmune disease, particularly rheumatoid arthritis (RA) and other related chronic, systemic and articular inflammatory diseases, is based upon current understanding of the pathogenic mechanisms involved. 1 The immune-based chronic inflammation, triggered by persistent bacterial, viral or autoantigens, or by an aberration in cytokine regulation of T-cells,2 forms the underlying pathophysiology of RA and other autoimmune diseases, such as systemic lupus erythematosus (SLB), psoriasis and psoriatic artMtis, atopic dermatitis, ankylosing spondylitis (AS) and chronic inflammatory bowel disease. Current therapy for RA is divided into two main categories dependent on the severity of the disease. Symptomatic relief of the effects of acute inflammation is readily accomplished using non-steroidal anti-inflammatory drugs (NSAIDs), now well-established as the primary line of treatment.3 In order t o slow or halt tissue destruction, and more specifically joint damage, agents now classified as disease-modifying antirheumatic drugs (DMARDs),~,~ such as gold, D-penicillamine (DPA) and the antimalarials, while not necessarily providing a cure, do retard the progress of the underlying disease in a less than predictable manned-8 by mechanisms as y e t only poorly understood.9~10 Since excellent reviews of the established NSAIDs3911 and DMARDs12s13 have recently appeared, this report will focus on potential DMARD candidates operating by a variety of mechanisms, with brief updates on agents cited here previously.l4,15 Where appropriate, application of these and similar drugs t o the treatment of other autoimmune disorders will be summarized. Recent DMARD Candidates - The difficulties inherent in discovering new DMARDs for RA and other autoimmune diseases are two-fold. First, there exists no single biological model of RA which can consistently predict DMARD-type activity. Secondly, an extended clinical trial of a potential DMARD double-blind against placebo is considered unethical since a statistical number of RA patients, whose disease is severe enough t o be otherwise treated, will go untreated for upwards of a year or more. Hence, most potential DMARDs are screened and clinically evaluated against the standard agents cited above. Alternatively, clinical agents of approved therapeutic utility in other autoimmune diseases are examined in the treatment of RA. A number of such crossover DMARD candidates are currently being evaluated. Sulfasalazine, useful in the treatment of ulcerative colitis,16,17 has been evaluated against other DMARDs in a number of RA studies, which indicate that long-term sulfasalaaine treatment of R A is a viable option, especially in patients resistant t o gold or DPA.18-20 A controlled double-blind study of etretinate, an oral retinoid used in the treatment of psoriasis, provided modest confirmation of previously uncontrolled studies in psoriatic artMtis.21 13-&- Retinoic acid and N-4-hydroxyphenylretinamide (fenretinide) both significantly reduced r a t adjuvant arthritis (rat AA).22123 The latter also suppressed streptococcal cell wall-induced arthritis.24 Another DMARD candidate, thalidomide, previously used as a sedative, hypnotic and antiemetic until withdrawal because of its severe teratological side effects, showed therapeutic utility in a form of leprosy, discovered while a patient ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21

Copyright 0 1986 by Academic Press, Inc. All rights of reproduction in any form reserved.

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received it as a sedative. Its anti-inflammatory properties in rat A A have prompted investigation into its DMARD potential for other autoimmune states.25~26 In a small, open PA clinical study, oral administration of thalidomide led to marked clinical improvement, which, in some cases, lasted long after discontinution of dosing. Adverse reactions, mainly associated with sedative effects, disappeared a t the completion of dosing.27 Although its extreme profile of side effects limits the potential use of thalidomide in BA, chemical modifications designed to retain the anti-inflammatory properties while eliminating adverse effects are ongoing.28 Finally, the biological and pharmacological profile of clobuzarit (Clozic.), a compound originally taken into clinical trials for atherosclerosis but later found to possess distinct DMARD properties in RA, has been summarized.29 A weak anti-inflammatory agent, clobuzarit inhibits the acute phase of rat AA, and may be acting by antiproliferative pathways. Adverse side effects observed in clinical trials have forced the withdrawal of clobuzarit from further consideration.30 Immunomodulatozy Drug T h e r a n - Perturbation of the delicate balance in the cellular and humoral immunoregulatory network results in a net expression of aberrant hyperreactivity in most autoimmune diseases.31 Thus, although immunosuppression might seem warranted for diseases of chronic inflammation and immunologic hyperreactivity, immunomodulation (immunoregulation), the dampening of hyperactive responses or enhancing defective negative influences, particularly through manipulation of the soluble mediators interleukins 1 and 2 (IL-1 and -2),32 is the required therapeutic strategy.33@ Two immunomodulators discussed here previously have gained limited approval for use in BA and other autoimmune diseases. Levamisole was shown to be superior to placebo35 and comparable to gold and DPA36 in two large RA trials, .ad of possible use in Chon's disease, herpetic keratitis37 and AS.38 Although patient withdrawals for toxicity reasons were frequent with levamisole, the side effects were found to be most rapidly reversible. Variations in the immunomodulatory effect of thymopentin CTP-5) and other thymic hormone derivatives approved for use in thymic deficiency, have been found to be dependent on the mode of administration,39 and there are conflicting reports on its clinical effectiveness in RA.40~41 Hypoxanthine derivatives hydroerythranol (NPT-15393, 1) and isoprinosine (INPX, 2) were found to enhance T-cell lymphocyte differeitiation and natural killer (NK) cell i~ctivity.42-~6One of these studies,45 carried out in patients with prolonged generalized lymphadenopathy, and other similar studies have prompted the investigation of INPX as a treatment in the early stages of acquired immune deficiency syndrome (AIDS). While INPX has been suggested as a treatment for RA47 and for SLB,48 no controlled trials have been carried out. In a small trial, however, INPX was found to be highly efficacious in the treatment of aphtous stomatitis, a result attributed to increased IL-2 production.49 Lobensarit (CCA, a), previously reported to inhibit rat AA, was examined in vitro a t non-toxic levels, and was found to block IL-1 and Ig production without effect on IL-2, and to induce y-interferon (1-IP).50 The therapeutic effect obsenred is postulated to be mediated by short-lived, thymus-derived lymphocytes,51 rather than macrophages.52 In a double-blind study, CCA was significantly superior to placebo, although a number of side effects were noted.53 The isoxazole HWA-486 (s), currently in clinical trials, prevents the onset of rat AA, provided therapy is initiated within the first 12 days

on 1

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of induction. After this point, it behaves as a classic NSAID, reducing inflammation only as long as administered.54 This response is correlated with improved lymphocyte response to both T- and B-cell mitogens and enhanced monocyte activity.55 Thiol-containing compounds based on the lead provided by DPA continue to be investigated. Tiobutarit (SA-96, 31, currently in advanced trials, differed from DPA in various immunopharmacological models, was more potent than DPA as an inhibitor of macropha e migration,56 and inhibited rat AA alone or in conjunction with indomethacin.57 A summary of the immunological profile58 and the results of a preliminary clinical trial59 have appeared. In in vitn, and viyi studies sodium diethyldithiocarbamate (DTC, Immuthiol@) enhanced T-cell specific functions in mice, and, in certain instances, IL-2 production in human T-lymphocytes,60 prompting limited studies in both AIDS61 and chronically infected patients.62 ADA 202-718 activated lymphocytes both in vim and in vivo, potentiating IL-2 and IF release in response to allogenic stimulation.63964 While it did not decrease swelling in rat AA, both pain and locally induced edema were reduced.64 Ristianol(2) has been registered as an Hs&coNH-w

(Ho4s-s4

H o / s c n 2 c N-

6

7

COOH 5

antiinflammatory immunoregulator in Europe, but no further information is available.65 In a six-month open trial of the angiotensin-converting enzyme (ACE) inhibitor captopril in RA, the results compared favorably with similar DPA or gold studies.66 A control study using enalapril, a non-sulfhydryl ACE inhibitor, was completely negative, suggesting that the observed antirheumatoid activity of captopril is due to the thiol group and not to ACE inhibition.67 Increased emphasis on immunomodulatory RA therapy has produced a number of new agents of widely varying structural types. PCE 20696 exhibits antiviral activity mediated by IF induction,68 and is orally active in three models of autoimmunity [rat AA, experimental allergic encephalomyelitis (EAE) and LF- 1695 Q), which potentiates suppressor T-cell NZBNF1 micel.69 mechanisms70 and induces both IL-1 and -2 synthesis,71,72 is being evaluated in

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clinical t r i a l ~ . ~ sTEI-3096 r~~ shown to suppress rat AA without effects on acute inflammation by restoration of suppressor T-cell activity,75 is currently in advanced clinical trials as an antirheumatic agent. Roquinimex (LS-2616, augmented mouse NK cell activity but did not increase serum IF levels,76 and enhanced responses t o T-cell mitogens and the delayed-type hypersensitivity (DTH) reaction.77 Lymphocytes from treated rats also showed enhanced IL-2 production, and restoration of immunosuppression characteristic of inhibition of IL-1 production. Ciamexon (BM 41.332, produces significant reduction of symptoms in rat AA, but differed clearly from standard antirheumatic agents. Its effect was attributed to a selective stimulation of the maturation of T-cells, such that helper T-cells cannot be developed and the differentiation to suppressor

a)

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T-cells is increased.78 An increase in DTH response79 and in the survival rate of immunocompromised mice80 have also been observed. Diphosphonate SR-41319 (19) is effective in the suppression of rat AA, likely by alteration of hydroxyadipate crystal disposition,81 and inhibits activities characteristic of IL- 1 stimulation.82 The immunomodulatory activity of retinoids has been reviewed,Bd and is likely the mechanism of action of etretinate and other retinoids in the treatment of psoriatic arthritis mentioned above. Immunosuppressive agents such as methotrexate (MTX), cyclophosphamide (CP) and aaathioprine (AT) are limited in their use due to associated toxicities,84 whereas non-cytotoxic agents offer another possibility in autoimmune therapy. Cyclosporin A (CS), an immunosuppressive agent approved for post-trans lant use,85 was highly efficacious as a potential DMABD in RA in two trlals,86,8 and has been proposed for use in psoriatic arthritis,88 SLB and insulin-dependent diabetes.89 The prospect of further modifications to CS to narrow its immunosuppressive profile has been proposed.90 Other synthetic immunosuppressive agents have also been shown t o be potential RA treatments. Mitoxantmne (14) inhibited helper T-cell function while enhancing suppressor activity,91 and suppressed the BAR reaction in rats.92 In rat AA, it displayed potency and efficacy comparable to MTX and greater than CP.93 ABAD (CL-232,468, &l a derivative of mitoxsntrone, is considerably more potent, inhibiting in vitro induction of alloreactivity and impairing both the proliferative response of lymphocytes to antigen and the generation of cytolytic T-cells. &Q, the suppression persisted for as long as 30 days after a single i.p. dose, consistent with the induction of suppressor T-cells as the mechanism of acti0n.~4 CL-246,738 (16) possesses a broad and & v i a immunomodulatory spectrum, including activation of NK cells and macrophages, and induction of IF.95~96 A structurally unrelated compound from the same group, CL-259,763 (17))stimulated macrophages and cytolytic T-cells.97 Sch-24,937 (18)suppressed the secondary response in rat AA, and was more potent than AT but less potent than CP in BAB. In contrast to many other immunosuppressive agents, it did not cause a reduction in circulating lymphocytes, indicating that its mode of action is not cytotoxic.98

Q

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15

R=NH./"H,

18 17

-

NSAIDs as Immunomodulatorv DMABDs Although NSAIDs are thought to operate by a common mechanism of action, observed interpatient differences in drug efficacy have raised questions about additional modes of anti-inflammatory action independent of prostaglandin (PG) synthetase inhibition.99 Since arachidonic acid metabolites are known to exert a range of immunoregulatory activities,100 the examination of the interrelationship of NSAIDs and other mediators of inflammation present in R A revealed a link between these agents and both humoral and cellular immune response. NSAID inhibition of the production of PGB2, the PG shown to tonically inhibit suppressor T-cell activity, allows suppressor T-cells to mature and control B-cell mediated rheumatoid factor production.1019102 In in vitro and yii studies, NSAIDs inhibited a number of markers of neutrophil activation, such as migration, superoxide generation and aggregation.103-105 The patterns of this inhibition vary from drug to drug, suggesting that NSAIDs may directly effect neutrophil activation by pathways independent of their shared inhibition of PG synthesis, such as their capacity to inhibit movements of calcium and enhance intracellular cyclic AMP

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(CAMP) levels.106

The combination of NSAID and DMARD profiles has been suggested as the ideal drug treatment for RA. A number of NSAIDs either established or under investigation have been found to display this profile. Of the acidic drugs, fenclofenac,l07 diclofenac sodium108 and the new agents piraaolac (MY-309, 191109 and RS-2131 ( a ) 1 1 0 display evidence of modest immunomodulatory activity. Wy-18,251 (211, originally identified as an antimetastatic agent with immunomodulatory activity,lll is similar to levamisole both in vitro and k m . 1 1 2 In acute anti-inflammatory studies, 22. demonstrated activity comparable to aspirin, but without antipyretic activity, and also inhibited rat AA. In & studies, it was a modest cyclooxygenase (CO) inhibitor lacking lipoxygenase (LO) inhibitory activity.113 Wy-41,770 (221,an anti-inflammatory agent devoid of GI side effects, was active in rat AA, but was a weak inhibitor of PG synthetase activity.114 In type 11 collagen-induced arthritis, 22 was more potent than indomethacin, methylprednisolone or DPA in reducing both hind paw edema and bone pathology.1159116

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Imidaaole- and thiaaole-containing compow, constitute another LASS of NSAIDs which possess immunomodulatory activity. Tiflamiaole (231,117 and structurally related to the platelet aggregation inhibitors flumiaolel f e n f l u m i a o l e , ~is~ ~a potent CO inhibitor which inhibits rat AA,120 and displays immunomodulatory activity in models of lymphocyte blast transformation and a hybrid structure derived from flumizole and SLB.1218122 Imidarothiazole levamisole, is an inhibitor of both phases of rat AA, and is active in a number of immunoregulato assays.123 Lotifarole (P-1686, XI124 and fanetirole 5 both weak CO inhibitors inactive in rat AA, display properties (CP-48810, of immunostimulants in other assays. Lotifaaole reduces DTH-induced pleurisy

3

in guinea pigs and oxasolone-induced contact hypersensitivity in mice. Panetizole specifically suppressed de novo IgE synthesis in atopic subjects. Both compounds show a stimulstory effect on T-lymphocytes. Another member of this chemical class, tomoxiprole (MDL-035, 2 1 , is active in rat AA and a potent PG synthetase inhibitor, but as yet no indication of immunomodulatory activity has been reported. 126,127 Antioxidants and Peroxvnenase Inhibitors - Arachidonic acid peroxidation products and reactive oxygen species, both responsible for inflammation and tissue damage, can be inhibited by a wide range of stnactural types. In addition to the nutritional antioxidants such as vitamins A and B, selenium and eicosapentaenoic acid, 12&129 many anti-inflammatory agents such as phenylbutarone, phenidonelb0 and CCAIS1 also act as general antioxidants. Interference with polymorphonuclear leukocyte ( P a - d e p e n d e n t oxygen

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intermediate generation has been suggested as the mechanism of action of thalidomide in RA.132 Four phenols recently prepared as antioxidants also exhibit marked anti-inflammatory activity. lS0 MK-447 (281 enhanced PGB2 synthesis, but exhibited marked antihypertensive and diuretic effects in man.133,134 ONO-3144 (39)acts a8 a eneral free radical scavenger and weak inhibitor of thromboxane synthetase.13t In clinical trials, 29 has been well tolerated, providing improvement in RA and lumbago with only minor GI side effects.136

R-830 (901, currently in clinical trials for topical treatment of inflammatory dermatoses,130 is orally active in rat AA, reversed passive Arthus reaction, and oxasolone-induced DTH, and inhibits both CO and L0.137 Reports on KME-4 (911 show a similar dual inhibitor profile of anti-inflammatory activity.138~139 The combination of the anti-inflammatory effect of CO inhibition with the potential immunomodulatory effects140 of LO inhibition has been proposed as a new treatment for RA.141~142 BW-540C (321 is active against carrageenan-induced edema in rats, and has been selected for evaluation in the treatment of psoriasis.143 CBS-1108 (831144 and CBS-1114 (941145 both exhibit a wide range of anti-inflammatory activities, especially in models in which CO inhibitors are not effective. The former exhibited a marked effect on leukocyte chemotaxis.146 The products of &LO, particularly leukotriene B4 (LTBq), are potent chemotactic agents which elicit a variety of acute147 and itnmune-based138 inflammatory responses. Both REV-5901 (Q51148*149 and RS-43179 (961150-152 were potent and selective 5-LO inhibitors both vitro and in vivo in the topical arachidonic acid-induced mouse ear edema m ~ d e l w -In~clinical ~ ~ trials, was effective as a topical treatment for psoriasis.156 The lipophilic benaoquinone AA-861 (571, also a selective 5-LO inhibitor, exhibited effects on asthmatic and inflammatory reactions.157 Although the reported LO inhibition by sulfrsalarine has been disputed,l58,159 one primary metabolite, 5-aminosalicylic acid, inhibits

5-LO16O and is thought to contribute to the first line effect in RA, while the other metabolite, sulphapyridine, is the active moiety responsible for second line effects.161 Both prodnrg162 and controlled delivery163,164 systems for 5-aminosalicylic acid release in ulcerative colitis treatment have been described. Although benoxaprofen has been demonstrated to be a LO inhibitor of some effect in psoriasis,l65 a small trial in ulcerative colitis proved unencouraging.166 Regulation of glutathione peroxidase, responsible for the decomposition of hydrogen peroxide into toxic oxygen species, was proposed as the mechanism of action for the novel organoselenium compound ebselen (PZ-51, Q8),167 but a more recent report indicates that 5-LO inhibition is the probable mechanism of action.168 Ancillary to the direct inhibition of &LO, the potential utility of antagonists of LTBa69 and platelet activating factorl70~171in inflammation has been discussed.

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Phomholipase and Phomhodiesterase Inhibitors - Glucocorticoids are known to exert their anti-inflammatory action by inhibition of the release of arachidonic acid from phospholipids by phospholipase A2 (PLA2).172 Detection of PLA2 in the sera and synovial fluids in RA173 reinforced the search for non-steroidal PLA2 inhibitors for chronic inflammation, even though the list of known inhibitors is short174 and recent detailed inhibition studies have raised questions concerning PLA activity.175 Timegadine (991, shown previously to inhibit rat AA, may exert its 2 -1 CO-LO inhibition by inhibition of PLA2.176 A small clinical trial has established its potential effectiveness in the remissive control of RA.177 Glucocorticoids inhibit PLA2 by stimulation of a 15 ldlodalton cell membrane protein variously referred to as macrocortin, lipomodulin or (the now preferred) lipocortin (LC), the endogenous inhibitor of PLA2.178 Highly purified LC exhibits steroid-like effects and an acute anti-inflammatory activity in rat carrageenan pleurisy edema.179~180 Monoclonal antibodies to LC reversed the biological effects of steroids in vim and to a certain extent in vivo.1818182 Cyclic nucleotides (CAMP or cGMP) are known to affect a multitude of biochemical regulatory processes, including the immune system. 183 Inhibition of the phosphodiesterases (PDBs) present in inflammatory cells would consequently raise intracellular levels of CAMP or cGMP, which in turn influence many cellular processes responsible for inflammation, including chemotaxis, aggregation and release of lysosomal enzymes and inflammatory mediators. Recently, nitraquaaone (TVX-2706, has been found to be a selective non-competitive inhibitor of cAMP PDB from a variety of cell sources, includixy PMN,184 possibly accounting for its potent anti-inflammatory activity.1 5 The observed immunomodulatory activity of J. may be due to selective inhibition of lymphocyte cGMP PDE.186 In vivo administration of CS was also found to raise cAMP levels in rat lymphocyte^.^

Inhibition of Comdement - The normally beneficial effects of the complement cascade, an immunostimulated process, lead to the adverse symptoms of chronic inflammation in autoimmune disease. Inhibition of the complement alternative pathway (CS transform6tion) or the terminal complement reaction (C5a activation) has been proposed as a possible treatment for RA, SLB, atopic dermatitis, psoriasis and other immune complex diseases.188,189 The sesquiterpene E-76COONa (41)interferes with C5a activation, and inhibits leukocyte migration and release of histamine in inflammatory models.190,191 Nafamstat mesilate (PUT-175, 421, a synthetic protease inhibitor, inhibits the alternative complement pathwag92 and has both rophylactic and curative effects on the development of.lupus nephritis in mice.lg3 Rosmarinic acid (491, a natural product exhibiting weak effects on mediators of acute inflammation, inhibits many inflammatory responses associated with complement activation, and is under development as a topical treatment for various autoimmune-based skin disorders. 194 Conclusion - Recent research has allowed a better definition of the basis of autoimmune disease, even though the precise details of the pathogenesis and etiology of most of these disorders remain unknown. Advances in immunology, in

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particular the complexity of the requirements for self-recognition, have shown that this internal regulatory system is subject to a myriad of controlling mechanisms and multiple pathways by which these mechanisms may be rendered abnormal.1 Pharmacological manipulation of even one of these regulatory systems might provide the means to control and eventually reverse the abnormal anti-self immune responses characteristic of autoimmune disease. I. 2.

3. 4.

5. 6. 7. 8. 9. 10. II. 12. 13. 14. 15. 16. 17. IS. 19. 20. 21. 22.

23. 24. 25. 26. .27.

28. 29.

M. 31. 32.

33.

u. 35.

36. 37.

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U. Klotz, K.E. Maier. C. Fisher and K.H. Bauer, Arznelm.-Forsch., 5. 636 (1985). K. Kragballe and 1. H w l i n , Arch. Dermatol.. 119. 548 (1983). C.J. Hawkey and D.S. Rampton, Prostaglandins E k o t r l e n e s kd., 10, 405 (1983). Res., lo, 397 (1985). M.J. Parnhmn S. Lmyck, N. Dereu, J. Winkelmann and E. Graf Adv,lnflainn. H. Safayhi, Tiegs and A. Wandel. B l a h . Pharmacol.. 34: 2691 (1985). J.H. hisser, A.F. K r e f t and A.J. Lewis, Annu. Rep. Ibd. C k . . 20, 71 (1985). M.C. Venuti, Annu. Rep. Ibd. Chm., 20, 193 (1985). 1.Y. Shen, Adv. I n f l m n . Res., 10, 376 (1985). S.J. F w h r and M.E. I*Connick.+ts Actions, 16. 58 (1985). U. Pruzanski, P. Vadas, E. Stafanski and M.B. Urowitr, J. Rheuinatol., 12, 211 (1985). G.J. Blackwell and R.J. Flower, Br. M. B u l l . , 39, 260 (1983). L.R. Ballou and W.Y. Cheung, Adv. Inflainn. Res.,70. 37 (1985). I. Mnfelt-Ronne and E. A r r i g o n l - b r t e l l i , B i d Pha-I, 31 2619 (1982). I. Caruso, M. Fuma a l l i , F. h t r o n e , M. Greco and L. BoccassinfCIin. Rheumatol., 2, 563 (1983). 8. Rothhut and F. Wusso-Marie, Adv. Inflamn. Res., 10, 360 (1985). Langham, L. P a m t e , P. Persico. N.C. G.J. Blackull. R. Carnuccio. M. Difbsa, R.J. Flaa 6

-

I d e n t i f c a t i o n of Conjugated Drug Metabolites The use o f MS/MS f o r the i d e n t i f i c a t i o n of conju ated (phase 11) metabolites was r e c e n t l y presented by Straub e t a,.'' I n t h e i r s t u d i e s , conjugated metabolites such a s the glucuronide of acetaminophen, the 4-sulfate e a t e r of acetaminophen, and the 3-sulfate e s t e r of dehydroisoandrosterone were i d e n t i f i e d i n crude phyeiological samples by f a s t atom bombardment (FAB) MS/MS. The fragmentation behavior of a number of glucuronide, s u l f a t e and glutathione ( G S H ) conjugates were investigated. 0-glucuronides were found t o undergo a n e u t r a l loss of 176 u, corresponding t o the loas of glucuronic acid. This n e u t r a l l o s s was observed i n both the p o s i t i v e and negative ion mode. Aryl s u l f a t e esters a r e detected by a n e u t r a l loss of 80 u (so3) i n both p o s i t i v e and negative ion modes. Alicyclic s u l f a t e e s t e r s are best detected by the parent scan of m/z 97 (HSOq-) i n the negative ion mode. Aryl-GSH conjugates a r e detected by the n e u t r a l loss of 275 u which correeponds to t h e mass of t h e peptide moiety, with cleavage of t h e S-peptide bond. CONCLUSIONS AND PROSPECTS

The MS/MS technique o f f e r s a general, e f f e c t i v e , and systematic method f o r the rapid i d e n t i f i c a t i o n of drug metabolites. By direct spect r a l i n t e r p r e t a t i o n of the step 5 daughter spectra, p o s s i b l e metabolite s t r u c t u r e s can be postulated without the use of pure reference standards.

Lee, Yost

Tandem Mass Spectrometry

Chap. 30

321

The use of this MS/MS method should make drug metabolite identification studies more rapid, convenient, and economical, as well as open up new areas of application (e.g. pharmacokinetic studies, and rapid screening of individual patients for metabolic abnormalities that affect drug therapy). The primary use of this MS/MS method is to provide a rapid survey of the major metabolites contained in a physiological sample. It is unlikely that this method would provide a complete description of all the rnetabolitee present in the sample. The rapid results of the M S D S method may also be used to supplement classical metabolite identification techniques by indicating the best position for isotope incorporation into the drug for radiotracer experiments. The use of chromatography in combinafor particularly tion with the MS/MS technique (GC/MS/MS and LC/MS/MS) Investigation of technidifficult problems has significant potential. ques such as desorption chemical ionization19, field desorption20, laser ~, atom bombarddesorption21 22 , secondary ion mass ~ p e c t r o m e t r y ~ faat ~' almost certainly enhance mentl*# 24, and thermospray i o n i ~ a t i o n ~ ~ - will the efficiency of this MS/MS technique for detection and identification of both phase I and phase I1 metabolites.

REFERENCES

1. 2. 3.

4. 5.

6. 7. 8.

9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

A. F r i g e r i o and E.L. G h i s a l b e r t i . Eds., "Mass Spectrometry i n Drug Metabolism," Plenum Press: New York. 1977. A. F r i g e r i o , Ed., "Recent Developments i n Mass spectrometry i n Biochemistry and Medicine," Plenum P r e s s , New York, 1978. B.J. Gudzinowicz and M . J . Gudzinowicz, Eds., "Analysis of Drug8 and Metabolites by Gas Chromatography-Mass Spectrometry," Marcel Dekker, VO1. 1-3, 1977, V o l . 4-5, 1978, V o l . 6, 1979, vol. 7 , 1980. T.A. B a i l l i e , A.W. Rettenmeier, L.A. Peterson and N. Castagnoli Jr., Annu. Rep. Med. Cham., 273-282 (1984). R.J. P e r c h a l s k i , R.A. Yost and B . J . Wilder, Anal. Chem., 1466 (1982). M.S. Lee, "The Rapid I d e n t i f i c a t i o n of Drug Metabolites by Tandem Mass Spectrometry." M.S. Thesis, University of F l o r i d a , 1985. F.W. McLafferty, Ed., "Tandem Mass Spectrometry." John Wiley & Sons, Inc., New York, 1983. J.V. Johnson and R.A. Yost, Anal. Chem., 57, 758A (1985). R.A. Yost and D.D. F e t t e r o l f , Mass SpeCtrOm. Rev.. 2. 1 (1983). R.G. Cooks and G.L. G l i s h , Chem. Eng. N e w s , 59 (Nov. 3 0 ) , 40 (1981). 280 (1981). F.W. McLafferty, Science, R.W. Kondrat and R.G. Cookr, Anal. Cham., 2, 81A (1978). F.W. McLafferty and F.M. Bockhoff, Anal. Chem., 69 (1978). R.A. Yost and C.G. Enke, Anal. Chem., 1251A (1979). R.A. Yost, C.G. Enke, D.C. McGilvery, D. Smith and J . D . Morrison, I n t . J. Mass Spectrom. Ion Phys., 0, 127 (1979). J.V. Johnson, M.S. Lee, M.R. Lee, H.O. Brotherton and R.A. Yost i n "Mass Spectrometry i n Biomedical Research." S.J. Gaskell, Ed., John Wiley & Sons: London, 1985. M.S. Lee, R.J. P e r c h a l s k i and R.A. Yost, Presented a t t h e 33rd Annual Conference on Mass Spectrometry and A l l i e d Topics, San Diego, C a l i f o r n i a (1985) Paper MOF8. K.M. Straub, C. Garvie and M. Davis, Presented a t the 33rd Annual Conference on Maas Spectrometry and A l l i e d Topics. San Diego, C a l i f o r n i a (1985) Paper TPG13. R.J. C o t t e r , Anal. Cham., 52. 1589A (1980). M. Przybylski, Fresenius Z . Anal. Chem., 402 (1983). R.J. C o t t e r , Anal. Chem.. 485A (1984). R.B. VanBreemen, J.-C. Tabet and R.J. C o t t e r , Biomed. Mass Spectrom., l J 278 , (1984). R.J. !Jay, S.E. M g e r and R.G. Cooks, Anal. Chem., 557A (1980). M. Barber, R.S. Bordoli, G . J . E l l i o t t , R.D. Sedgwick and A.N. T y l e r , Anal. Cham., 54, 645A (1982). C.R. Blakley and M.L. Vestal, Anal. Cham., 55, 750 (1983). T. Covey and J.D. Renion. Anal. Chem.. 55, 2275 (1983). D.J. Lilmrato, C . Penselau, M.L. Veatal and A.L. Yergey, Anal. Chem. 1741 (1983).

19,

s,

3,

z.

z,

so,

315,

z.

-

z,

This Page Intentionally Left Blank

Section V I I .

Worldwide Market Introductions

Editor: Richard C. Allen, Hoechst-Roussel Pharmaceuticals Inc. Somerville, New Jersey 08876 Chapter 31. To Market, To Market

- 1985

Richard C. Allen, Hoechst-Roussel Pharmaceuticals Inc., Somerville, NJ 08876 The new chemical entities (NCEs) for human therapeutic use introduced into the world marketplace for the first time in 1985 were about equal in number to those introduced in 1984.1 Although not included in this chapter, a small, but increasing number of biologicals (interferons, hormones, etc.), derived through recombinant DNA research, are being launched. The United States topped the list of NCE originators in 1985, followed by Japan. West Germany had the most first time NCE ihtroductions, followed closely by Japan and Italy. A record number of NCEs were approved and marketed in the United States during 1985.2 None of these, however, was a first time introduction. From the following compilation of 1985 first time worldwide NCE introductions, imipenem/cilastatin, levobunolol hydrochloride, quazepam and sulconazole nitrate had, by the year's end, been either marketed or approved for marketing in the US.

Acipimox (hypolipidemic)3,4 Country of Origin: Italy Originator: Erbamont First Introduction: Italy Introduced by: Erbamont Trade Name: OLBET-

/N\ /CO2H

1

t' CH/.y

0

Acipimox is a hypolipidemic agent related to nicotinic acid with pronounced, longlasting antilipolytic activity. In addition to its lipid lowering activity, i t produces a beneficial elevation of the anti-atherogenic high density lipoprotein subfraction, HDLz. Alclome tamne Dipropionate (topica1 ant iin f lam ma tory)596 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

USA Schering Chile; W. Germany Mering VADERM

Alclometasone dipropionate is a potent topical steroid useful in the treatment of atopic dermatitis and psoriasis. ANNUAL REPORTS IN MEDICINAL CHEMISTRY-21

Copyright 0 1986 by Academic Press, Inc. All rights of reproduction in any form reserved.

324

Section V I I

- Worldwide Market Introductions

Allen, Ed.

Astromici Sulfate ( a n t i b i ~ t i c ) ~ , ~ Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

Japan Kyowa Hakko Japan Kyowa HakLo FORTIMICIN

Astromicin sulfate is a pseudodisaccharide aminoglycoside antibiotic with a spectrum comparable to amikacin. It is active against many gentamicin and amikacin resistant bacteria expressing aminoglycoside-modifying enzymes, with the exception of aminoglycoside 3-acetyltransferase, ~opindol01(antihypertensive)9910 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

Switzerland sandoz Switzerlapd

H

do\

APH3

t n i i

Sdoz

SANDONORM

Bopindolol is a potent, long-acting, non-selective B-adrenergic blocker related to pindolol and useful in the treatment of hypertension. Unlike many other agents of this type, it appears to have negligible effects on serum lipoproteins. B~nazoeinHydrochloride (antihypertensive)ll,12 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

Japan Eisai Japan

E M DETANTOL

Bunazosin hydrochloride is a selective al-adrenergic antagonist related to prazosin and useful in the treatment of hypertension.

Buspirone Hydmchloride (anxiolytic)l3,14 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

USA Mead Johnson W. Germany Bristol BESPAR

-.\,.-.’P

0-./

‘0-0

0-0

Buspirone hydrochloride is an anxiolytic agent indicated for the management of anxiety disorders with or without accompanying depression. In contrast to the benzodiazepines, buspirone does not interact with alcohol, and lacks sedative, anticonvulsant, and muscle relaxant effects, and abuse potential.

To Market, t o Market

Chap. 31

- 1985

Allen

325

Camostat Mesylate (prot ease inhibitor) 15, 16 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

Japan On0

H2Nk-m4*-'*-C0

Japan

-0'

2

\m=m'

/.-\

\ m=m

'.--CH2C02CH2CON(CH3 / 'C H R S O ~ H

)*

- -

On0

FOIPAN

Camostat mesylate is a broad spectrum protease inhibitor useful in the treatment of chronic pancreatitis.

Country of Origin: Japan Originator: Topama First Introduction: Japan Introduced by: Toyama; Kaken Trade Name: TOMIPORAN; KEIPERAZON Cefbuperazone sodium is a B-lactamase resistant, third generation cephalosporin with a serum half-life of about 1.5 hours. Cefpiramide Sodium (antibiotic)l9,20 w3

bH

Originator: Sumitomo Introduced by: Sumitomo, UpjoYamanouchi, Banyu

Country of Origin: Japan First Introduction: Japan Trade Name: SEPATREN; SUNCEFAL

Cefpiramide sodium is a third generation cephalosporin with exceptionally good @ activity. Its relatively long serum half-life (-4.5 hours) allows once to twice-daily dosing.

& antipseudomonal

Cibenzoline (antiarrhythmic) 1,22 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

France Hexachemie France UPSA CIPRALAN

A

7

*=*\ * ,m & ,

m-m-• /\ / \m=m

/

\

m\m-m,m

Cibenzoline is a structurally novel, class I (quinidine-like) antiarrhythmic agent. It has additional properties of class ID and class IV compounds, delaying repolarization and antagonizing the positive inotropic effects of calcium.

326

Section V I I

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Allen , Ed.

Cimetropium Bromide (antispa~modic)~3 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

Italy deAngelini Italy deAngelini ALGINOR

B r-

+

Cimetropium bromide is an analog of the anticholinergics methscopolamine, ipratropium and oxitropium bromides.24 It is reported to be useful in the treatment of increased tone and motility of the gastrointestinal, biliary and urogenital tracts. Ciprofibrate (hypolipidemic)2592 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

USA Sterling-Wintbrop France Sterling-Wiuthrop

2H

c1/*\CL

IJPANOR

Ciprofibrate is a potent, long-acting hypolipidemic agent related to clofibrate, bezafibrate and fenofibrate. It is effective in types IIa, IIb, IIX and IV hyperlipoproteinemias, and produces a beneficial elevation of the anti-atherogenic HDL. Diacereiu (antirheumatic)27-29 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

Italy Roter Italy Roter ARTRODAR

/.\ T B

CH3CQ2

f

oCocH3

I*\/*\

t\*/ .t\cooH

8

Diacerein is a disease-modifying antirheumatic drug (DMARD), reported to be useful in the treatment of various inflammatory conditions, including osteoarthritis. It forms water soluble chelates with calcium and copper, acting ultimately to reduce the activity of lysosomal enzymes and decrease the formation of rheumatoid factor. Doxefazepam (hypnotic)30,31 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

QH

Italy Schiappatelli Italy

Schiapparelli

DOXAPJS

Doxefazepam is a benzodiazepine hypnotic somewhat more potent than flurazepam.

Chap. 31

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To Market, t o Market

1985

Allen

327

Doxofylline ( b r o n ~ h o d i l a t o r ) ~ ~ , ~ ~ Country of Origin: Italy Originator: ABC S.p.A. First Introduction: Italy Introduced by: ABC S.p.A. Trade Name: ANSIMAR

Doxofylline, a xanthine bronchodilator related to theophylline, is useful in the treatment of asthma and similar bronchospastic disorders. It has minimal activity on intestinal smooth muscle and the cardiovascular system, and is reportedly devoid of the behavioral effects of theophylline.

EuprostiI (antiulcer)34,35 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

H

USA Syntex

Mexico Syntes GARDRIN

/*,*/rnCHs \

\.=. >.

4-h0/0\0/0~o/0-0\ € I HO'

H H

Enprostil is one of three, orally-active prostaglandins (see rnisoprostol and rosaprostol) launched this year for the treatment of gastric and duodenal ulcers. An allenic PGE2 derivative, enprostil is both antisecretory (acid, gastrin) and cytoprotective. Etodolac (antiinflammatory)36-38 0

Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

USA Ayerst Colombia; United Kingdom Ayerst

LODINE

\

H

t4"iA./

t 0\0/0-C02H

II

'p

'\,/O-'\,/O

Etodolac (etodolic acid) is a non-steroidal antiinflammatory/analgesic agent useful in the treatment of various inflammatory conditions, including rheumatoid and osteoarthritis. Famotidine (antiulcer)39,40 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

Japan Yamauouchi Japan Yamanouchi GASTER

Famotidine is a histamine H2-antagonist more potent than cimetidine and ranitidine. Administered once or twice daily, i t is useful in the treatment of gastric, duodenal and anastomotic ulcers, upper gastrointestinal tract hemorrhage, reflux esophagitis and Zollinger-Ellison syndrome. Like ranitidine, it is lacking in antiandrogenic effects.

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- Worldwide Market Introductions

Allen, Ed.

Flupirthe M a l e a t e (analgesic)41,42 /NHC0ZC2%

/"ZH

.R

Originator: Chemiewerk Homburg (Degussa) Country of Origin: W. Germany Introduced by: Chemiewerk Homburg (Degussa3 First Introduction: W. Germany Trade Name: KATADOLAN Flupirtine maleate is a centrally-acting, non-addicting analgesic agent somewhat more potent than aspirin, paracetamol and pentazocine. It is reported to be useful in the treatment of postoperative and dental pain. Imipenem/Cilastatin (antibiotic)43,44 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

Imipenem is a chemically stable thienamycin derivative with an antibacterial activity that is broader in spectrum and of greater potency than most of the third generation cephalosporins. Combination with cilastatin, an inhibitor of renal brush-border dehydropeptidase-I, increases both urinary and plasma levels of imipenem. Ketauseriu (antihypertensive)4%46 Country of Origin: Belgium Originator: Janssen First Introduction: Argentina Introduced Trade Name: by: SEREFREX Janasen

H

R

/*h

T

Ap /*-*\*+

8

/

a ' * ~ * ' a ~ C H z C H 2 < a - **-• ~*-C~\

C.

Ketanserin is an antihypertensive agent with antagonist properties at both the serotonin-S2 and q-adrenergic receptors. Its mechanism of action, while still controversial, may involve interactions at both of these loci. Levobunolol Hydrochloride ( a n t i g l a ~ c o m a ) 4 ~ , ~ ~ Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

USA Warner Lambert

W. Germany Allergan VISTAGEN LIQUIFILM

/*-a\a o=a\.=a/

-HC1

' )-OcH, SHHCH2NHC(CH3 L/

13

Levobunolol hydrochloride is a non-selective B-adrenergic blocker useful in the treatment of glaucoma. Worldwide, it represents the sixth B-blocker t o be launched for this indication.

Chap. 31

- 1985

TO Market, t o Market

Allen

329

Malotilate (hepatopr~tective)~% 50 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

'

Japan Nihm Nohyaku Japan Daiichi Seiyaku KANTEC

p\

II \S

co2a(m3)2

1*='COZCH(CH3)?

Malotilate is a hepatoprotective agent reported to be effective in the treatment of cirrhosis, chronic hepatitis and similar liver disorders. It appears to improve hepatic function by increasing blood and bile flow and improving protein synthesis.

Mefloquine Hydrochloride (antimalarial)51 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

YF3

USA

y\ A F F 3

Walter Reed

Thailand Hoffmanu-La Roche

FANSIMEF

T f i T 4.

b-0.

* HC 1

t / O b

Zmf Mefloquine hydrochloride is an erythrocytic schizonticide useful, in combination with sulfadoxine and pyrimethamine, in the prophylaxis and treatment of malaria. Administered once weekly, the combination is effective against pathogens resistant to other agents. Miokamycin (antibiotic)%53 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

Japan

3

Meiji Seika Japan Meiji Seika

0=.

MIOCAMYCIN

Miokamycin (midecamycin acetate) is a macrolide antibiotic useful in the treatment of respiratory tract, dermatological and surgical infections due to grampositive bacteria and mycoplasmas. Misoprosto1 (antiulcer)3%54-56 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

USA Searle Mexico Searle CYTOTEC

(216 R,S) Misoprostol is an orally-active PGEl analog useful in the treatment of gastric and duodenal ulcers. As with other agents of this type, misoprostol may prove useful as a gastric cytoprotective when administered concurrently with irritating drugs such as nonsteroidal antiinflammatories.

3 30

Section VII

- Worldwide Market Introductions

Allen, Ed.

Mupirocin (topical antibiotic)57-59

Country of Origin: United Kingdom First Introduction: United Kingdom Trade Name: BACTROBAN

Originator: Beecham Introduced by: Beecham

Mupirocin (pseudomonic acid A) is an antibiotic produced by Pseudomonas fluorescens. It is useful in the treatment of dermal infections, especially those involving S. aureus and 5. epidermidis. Nabumetone (antiinflarnrnat~ry)~~-~~ Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

United Kingdom Beecham kelaud Beecham RELIFEX

/\

T

D

f a /e\b/*\'

t

t

/*\,/'\,/*

a30

Nabumetone is a non-acidic, nonsteroidal antiinflammatory agent formally related to naproxen. Its main circulating metabolite is 6-methoxy-2-naphthylacetic acid (a-nornaproxen). Administered once daily (T%* 30 hrs), nabumetone is reported to be effective in the treatment of rheumatoid and osteoarthritis. Nimesulide (antiinf lam matory) 64-67 Country of Origin: Originator: First Introduction: Introduced by: Trade Namk:

NHSO 2 CH 3 I

USA Riker Portugal Lab Biofarma MESULIDE

/ t O p 3 H 5

t

B '

!

/

Nimesulide is a nonsteroidal antiinflammatory/analgesic agent useful in the treatment of rheumatoid arthritis, as well as acute inflammation such as that induced by periodontal surgery or urinary tract infections. Nimudipine (cerebral vasodilator) 68~69 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

W. Germany

/'\,PO2

W. Germany Bayer NIMOTOP

I .\ yo/*\ T

Bayer ( CH3 12 CHO 2

t

II

/

n

/CO2 CH2 CHzOCH 3

Nimodipine is a cerebral vasodilating calcium antagonist related to nifedipine. It is indicated for the prophylaxis and treatment of neurological deficits due to cerebral vasospasm after subarachnoid hemorrhage.

-

To Market, t o Market

Chap. 31

1985

Allen

211

Nitrendipine (antihypertensive)70,71 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

W. Germany Bayer W. Germany

Barer BAYOTENSIN

'\

t

/'

/'\ /'OZCZH5

cH302\

A

A

Nitrendipine is a vasodilating, dihydropyridine calcium antagonist. Its prolonged therapeutic effect in comparison to nifedipine makes i t useful in the once to twice daily treatment of hypertension.

Ofloxacin ( a n t i b a ~ t e r i a l ) ~ ~ , ~ ~ Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

Japan Daiichi Seiyaku W. Germany Hoechst AG TARIVID

F\o/o\

t

II

1

/ \'/ C02H II

3

Ofloxacin is an antibacterial agent with increased potency in comparison to the prototype third generation quinolone, norfloxacin.24 It has a broad spectrum of activity against gram-positive and gram-negative bacteria and is useful in the treatment of kidney, genitourinary, and upper respiratory tract infections. Pefloxacin Mesylate (antibac t eria1)74,75 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

France Roger Bellon (Rhone-Poulenc) France Roger Bellon (Rhone-Poulenc) PEFLACINE

F\o/o\

,(:y

(3%

/

P

f

'

/'\/ C02H 'm3SO+jH

'"'x,

CH

Pefloxacin mesylate is a broad-spectrum, third generation quinolone antibacterial agent useful in the treatment of infections due to a variety of organisms, including methicillin-resistant S. aureus. A major metabolite of pefloxacin is norfloxacin.24 Progabide (anticonvulsant)76-78 Country of Origin: France First Introduction: Originator: Synthelabo France Introduced by: Synthelabo Trade Name: GABRENE

/'\ i ; !

PH

do\*' ).=N-CH2CH2CH2CONH,

pi

'\

/'

El Progabide is a broad-spectrum anticonvulsant agent indicated for the treatment of a wide variety of seizure disorders. Synthesized as a GABA-prodrug, anticonvulsant activity appears due to the parent drug and its acid metabolite, as well as to GABAmide and GABA liberated therefrom.

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Section VII

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Allen, Ed.

Quazepam (hypnotic)79-80 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

USA Scheriag Netherlamia Schering

/\ P

SELEPAM

t f i

Quazepam is a rapidly acting, short term hypnotic reported to exhibit a low incidence of side effects.

Rifaximin (antibiotic) 81s82 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

Italy Alfa Italy schiapparelli RIFACOL

Rifaximin is a non-absorbable rifamycin derivative useful in the treatment of intestinal diarrhea. It displays good activity against a wide spectrum of bacteria, including Salmonella spp., 5. aureus, and E. coli. &maprosto1 (antiulcer)8344

Country of Origin: Originator: First Introduction: Introduced by: Trade Name:

Italy Tnatituto Biochemico Italiano Italy h t i t u t o Biochemico Italiano

OH .>-p

io\o/o\o/o COOH

\