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Medicinal
Chemistry Advances
Proceedings of the Seventh International Symposium
on Medicinal Chemistry, Torremolinos, Spain
2 - 5 September 1980
Edited by
FEDERICO G. DE LAS HERAS
and
SALVADOR VEGA
Institute* de Qu/mica Medica, Madrid, Spain
PERGAMON PRESS
OXFORD · NEW YORK ■ TORONTO ■ SYDNEY ■ PARIS ■ FRANKFURT
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Copyright © 1981 Pergamon Press Ltd.
All Rights Reserved. No part of this publication may be
reproduced, stored in a retrieval system or transmitted in
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publishers.
First edition 1981
British Library Cataloguing in Publication Data
International symposium on Medicinal Chemistry
(Chemistry : 7th : 1980: Torremolinos)
Medicinal chemistry advances.
1. Drugs - Congresses
I. Title II. Heras, Federico G, de las
III. Vega,Salvador
615'. 1 RM300
ISBN 0-08-025297-4
In order to make this volume available as economically and
as rapidly as possible the authors' typescripts have been
reproduced in their original forms. This method unfor
tunately has its typographical limitations but it is hoped that
they in no way distract the reader.
Printed in Great Britain by A. Wheaton Et Co. Ltd., Exeter
List of Contributors
R. Acher J. H. Burchenal
Laboratory of Biological Chemistry Memorial Sloan-Kettering Cancer Ceni
University of Paris VI New York, N.Y. 10021, U.S.A.
96, Boulevard Raspail
7 5006 Paris, France. A. Burger
Department of Chemistry
M.A. Alonso University of Virginia
Departamento de Microbiologia Charlottesville, Virginia 22901, U.S.
Centro de Biologia Molecular
Universidad Autonoma S. Caccia
Canto Blanco, Madrid-34, Spain. Istituto di Ricerche Farmacologiche
"Mario Negri"
E.J. Ariens Via Eritrea, 62
Institute of Pharmacology and 20157 Milano, Italy.
Toxicology
University of Nijmegen J.G. Cannon
Geert Grooteplein N 21 Division of Medicinal Chemistry and
P.O. Box 9101 Natural Products
6500 HB Nijmegen, The Netherlands. College of Pharmacy
The University of Iowa
C. Arnau Iowa City, Iowa 52242, U.S.A.
Facultat de Medicina
Universität Autonoma de Barcelona R. Carbo
Bellaterra, Barcelona, Spain. Institut Quimic de Sarriä
Barcelona-17, Spain.
G. Bartholini
Synthelabo (L.E.R.S.) L. Carrasco
58, rue de la Glaciere Departamento de Microbiologia
75013 Paris, France. Centro de Biologia Molecular
Universidad Autonoma
J. Benveniste Canto Blanco, Madrid-34, Spain.
INSERM U 200
Clamart/Paris, France. P. Chandra
Gustav-Embden-Zentrum der
A. Beres Biologischen Chemie Abteilung für
Division of Medicinal Chemistry Molekularbiologie
and Natural Products Universität Frankfurt (Main)
College of Pharmacy Frankfurt 70, Federal Republic of
The University of Iowa Germany.
Iowa City, Iowa 52242, U.S.A.
J. Chauvet
D. Brandenburg Laboratory of Biological Chemistry
Deutsches Wollforschungsinstitut University of Paris VI
Aachen, Federal Republic of 96, Boulevard Raspail
Germany. 75006 Paris, France.
ix
List of Contributors
M.T. Chauvet J. M. Fernandez-Sousa
Laboratory of Biological Chemistry Antibioticos, S.A.
University of Paris VI Bravo Murillo, 38
96, Boulevard Raspail Madrid-3, Spain.
75006 Paris, France.
J.J. Fox
M. Chignard Laboratory of Organic Chemistry
Institut Pasteur Sloan Kettering Institute
Paris, France. for Cancer Research
Rye, New York, 10580, U.S.A.
E. Clementi
IBM Corporation S. Garattini
Dept.B-28, Bldg. 703-1 Istituto di Ricerche Farmacologiche
P.O. Box 390, "Mario Negri"
Pough Keepsie, N.Y. 12602, U.S.A. Via Eritrea, 62
Milano 20157, Italy.
K. Comai
Roche Research Center M. T. Garcia Lopez
Hoffmann-La Roche Inc. , Instituto de Quimica Medica
Nutley, New Jersey 07110, U.S.A. Juan de la Cierva, 3
Madrid-6, Spain.
A. P. Corfield
Biochemisches Institut P.P. Garcia de Jalon
Christian-Albrechts-Universität Departamento de Farmacologia
D-2300 Kiel, Federal Republic Facultad de Medicina
of Germany Universidad Complutense
Madrid-3, Spain.
F. G. de las Heras
Instituto de Quimica Medica A. Giner-Sorolla
Juan de la Cierva, 3 Memorial Sloan-Kettering Cancer Center
Madrid-6, Spain. New York, N.Y. 10021, U.S.A.
G. de Stevens A. Giräldez
Department of Chemistry Abello, S.A.
Drew University Julian Camarillo, 8
Madison, New Jersey, U.S.A. Madrid-17, Spain.
F.P. Doyle F. Grande
Beecham Pharmaceuticals Instituto de Investigacion Bioquimica
Research Division y de Nutricion, Fundacion Cuenca
Brockham Park Villoro y Departamento de Bioquimica
Betchworth Facultad de Ciencias
Surrey, U. K. Universidad de Zaragoza
Zaragoza, Spain.
C. Fernandez-Puentes
Departamento de Microbiologia L. G. Humber
Centro de Biologfa Molecular Chemistry Department
Universidad Autonoma AYERST Research Laboratories
Canto Blanco, Madrid-34, Spain. 1025 Laurentien Blvd.
Saint-Laurent, Que.
P.O. Box 6115, Montreal, Canada.
List of Contributors
E. Kyburz T. Mennini
Pharmaceutical Research Department Istituto di Ricerche Farmacologiche
F. Hoffmann-La Roche & Co., Ltd. "Mario Negri"
CH-4002 Basle, Switzerland. Via Eritrea, 62
20157, Milano, Italy
J.C. Lacal
Departamento de Microbiologia B.W. Metcalf
Centro de Biologia Molecular Merrell Research Center
Universidad Autonoma Division of Richardson-Merrell Inc.,
Canto Blanco, Madrid-34, Spain. 2110 East Gelbraith Road
Cincinnati, Ohio 45215, U.S.A.
G. Lambrecht
Department of Pharmacology S. Moncada
Faculty of Biochemistry, Pharmacy Department of Prostaglandin Research
and Food Chemistry Wellcome Research Laboratories
University of Frankfurt Langley Court, Beckenham
Theodor-Stern-Kai 7, Gebäude 75A Kent, BR3, 3BS, U.K.
D-6000 Frankfurt, Federal Republic
of Germany. J. S. Morley
Imperial Chemical Industries Ltd.
J.P. Le Couedic Pharmaceuticals Division
INSERM U 200 Alderley Park
Clamart/Paris, France. Macclesfield, Cheshire, U.K.
T. Lee A. Munoz
Division of Medicinal Chemistry and Departamento de Microbiologia
Natural Products Centro de Biologia Molecular
College of Pharmacy Universidad Autonoma
The University of Iowa Canto Blanco, Madrid-34. Spain.
Iowa City, Iowa 52242, U.S.A.
E. Mutschler
J.P. Long Department of Pharmacology
Department of Pharmacology Faculty of Biochemistry, Pharmacy
College of Medicine and Food Chemistry
The University of Iowa University of Frankfurt
Iowa City, Iowa 52242, U. S.A. Theodor-Stern-Kai 7, Gebäude 75A
D-6000 Frankfurt, Federal Republic
C. Lopez of Germany.
Memorial Sloan-Kettering Cancer
Center F. Numano
New York, N.Y. 10021, U.S.A. Department of Internal Medicine
Institute for Cardiovascular Diseases
C. Lugnier Tokyo Medical and Dental University
Laboratoire de Pharmacodynamie Yushima 1-chome, Bunkyo-ku
Universite Louis Pasteur Tokyo 113, Japan.
CNRS ERA 787
INSERM FRA 53, B.P. 10 F. Pelayo
67048 Strasbourg, France. Departamento de Farmacologfa
Facultad de Medicina
Universidad Complutense
Madrid-3, Spain.
xi
List of Contributors
C. Petrongolo J.C. Stoclet
Laboratorio di Chimica Quantistica Laboratoire de Pharmacodynamie
ed Energetica Molecolare Universite Louis Pasteur
Pisa, Italy. CNRS ERA 787, INSERM FRA 53
B.P. 10, 67048 Strasbourg, Prance.
M. M. Puig
Departamento de Farmacologia A.C. Sullivan
Facultad de Medicina Roche Research Center
Universidad de Murcia Hoffmann-La Roche Inc. ,
Murcia, Spain. Nutley, New Jersey 07110, U.S.A.
G. Ranghino J. Triscari
Istituto di Ricerche G. Donegani Roche Research C enter
Novara, Italy. Hoffmann-La Roche, Inc.
Nutley, New Jersey 07110, U.S.A.
D.J. Roberts
Research Institute H. Tschesche
Laboratorios Almirall Faculty of Chemistry
Cardoner, 68-72 Biochemistry Department
Barcelona-12, Spain. University of Bielefeld
Federal Republic of Germany.
R. Samanin
Istituto di Ricerche Farmacologiche J.R. Vane
"Mario Negri" Department of Prostaglandin Resarch
Via Eritrea, 62 Wellcome Research Laboratories
20157 Milano, Italy. Langley Court
Beckenham, Kent BR3. 3BS, U.K.
R. Schauer
Biochemisches Institut B.B. Vargaftig
Christian-Albrechts-Universität Institut Pasteur
D-2300 Kiel, Federal Republic Paris, France.
of Germany.
D. Vazquez
R. Scordamaglia Centro de Biologia Molecular, C.S.I.C.
Istituto di Ricerche G. Donegani and U.A.M., Facultad de Ciencias
Novara, Italy. Canto Blanco, Madrid-34, Spain.
D. Shugar J.W. Wasley
Institute of Biochemistry and Ciba-Geigy, Pharmaceuticals Division
Biophysics Summit, N.J. 07901, U.S.A.
Academy of Sciences
02-532 Warszawa, Poland, and K.A. Watanabe
Dept. of Biophysics, Institute of Laboratory of Organic Chemistry
Experimental Physics Sloan-Kettering Institute for Cancer
University of Warsaw Research
02-089 Warsaw, Poland. Rye, N.Y. 10580, U.S.A.
B.J.R. Whittle
Department of Prostaglandin Research
Wellcome Research Laboratories
Langley Court
Beckenham, Kent BR3-3BS, U.K.
xii
Introduction
The Vllth International Symposium on Medicinal Chemistry was held in the
Palace of Congresses of Torremolinos, Malaga, Spain, from the 2 nd to the 5th
September 1980, and was organized by the Sociedad Espafiola de Quimica Tera-
peutica. The Symposium was attended by over 700 participants from 34 countries
and consisted on 2 plenary lectures, 36 invited lectures on ten selected topics and
224 communications as posters.
In a moment like this of increasing difficulties for the research in Medicinal
Chemistry we considered useful to have the views of qualified speakers about the
present situation of drug design, discovery and development. Prof. A. Burger
and Dr. F.P. Doyle talked in their plenary lectures about this subject from an
academic and a pharmaceutical industry point of view, respectively.
The ten topics selected: Nucleosides in chemotherapy, Theoretical
approaches to Medicinal Chemistry, Platelets and antithrombotic agents,
Receptors, Antiviral agents, Antilipidemic agents, Respiratory system, Central
nervous system, Enzyme inhibitors and Bioactive peptides, covered a wide field
of interest within Medicinal Chemistry. In an attempt to bring together the
different people involved in the discovery and development of drugs, the invited
speakers were Medicinal Chemistry active chemists, pharmacologists, biochemists
and physicians from both academic and industrial fields.
We want to express our gratitude to the members of the Organising Committee
who chose the lectures of this Symposium and to the members of the Scientific
Advisory Committee who helped them. Also to Mrs. Natividad Palacios de la Vega
for her help in the preparation of this volume.
R. Madronero
Chairman of the Organising Committee
F.G. De Las Heras and S. Vega,
Editors
Xlll
Current Options in Drug Design
A. Burger
Department of Chemistry, University of Virginia, Charlottesville,
Virginia 22901, USA
ABSTRACT
The principal goals of medicinal chemistry are the discovery of "lead" compounds,
their molecular modification, the preparation of drugs, and the explanation of
their molecular mode of action. "Lead" compounds are discovered by screening but
if a biochemical aberration can be established as an etiological factor in a
given disease, metabolites involved in the biochemical lesion can become "leads".
In a few cases, the reactions of a drug with active receptor sites, especially
enzymic cofactors, have been analyzed and serve as guides for designing "lead"
compounds. Molecular modification can be based rationally on bioisosterism.
Some rules of bioisosterism wiere expanded and updated and have also received some
aid from quantitative structure-activity studies.
KEYWORDS
Bioisosterism; irreversible inhibitors; "lead" compounds; medicinal chemistry;
metabolic blockade; metabolite analogues; molecular modification; monoamine
oxidase inhibitors; pharmacological guidelines to drug design; quantitative
structure-activity relationships; receptors; screening; suicide enzyme inhibitors;
transition state analogues.
INTRODUCTION
It is a festive occasion for me to participate in the opening of the 7th
International Symposium on Medicinal Chemistry. Thirty-two years ago we started
to schedule symposia on medicinal chemistry in the U.S.A., but even in 1951
patient persuasion was needed to be allowed to call the first edition of my book
on medicinal chemistry by that title, since medicinal chemistry was still confused
with analytical and diagnostic methods of chemical control in hospitals. Today we
feel happy that our topic is approaching the scope of an exact science, with a
record of proud achievements in the conception, development and understanding of
hundreds of important drugs in almost all fields of therapy. If the literature
of the last few years is a portent of the future we can be highly optimistic about
the role medicinal chemistry will play in collaboration with other experimental
therapeutic sciences and in the service of medicine.
Our role in this team effort is to create and furnish medicinal agents for
biochemical and biological experimentation, and for therapeutic or prophylactic
use in disease. This used to be done by trial and error or by serendipity. These
1
A. Burger
are wasteful methods but they have stood us in good stead in the past when
augmented by intuition and experience in a specialized confine of chemical
structures. It has been said in this regard that "ideas have to be fruitful, they
do not have to be completely right" (Nathan, 1976).
As we have unraveled a few of the biochemical events in normal and abnormal
physiology, it has become possible to limit screening programs to analogues,
however structurally far-fetched, of natural metabolites. Educated guesses made
by one medicinal scientist or a committee of several investigators are of some
value in such selections. Indeed, one no longer wastes time on trying to solve
therapeutic problems in areas of disease where no initial biochemical guidelines
are available.
THE DISCOVERY OF "LEAD" COMPOUNDS
The most difficult problem of medicinal chemistry is the discovery of "lead"
compounds. Only in very few cases have "lead" compounds been elaborated by
deliberate drug design. One such example is the planning of pyridine-2-aldoxime
methiodide (2-PAM) in nucleophilically reversing phosphate ester inhibition of
acetylcholinesterase (Wilson, 1955). Another approach is the design of irrever
sible enzyme inhibitors whose alkylating groups might react with regions not
directly involved in the active sites of an enzyme (Baker), 1967). A suggestion
for partial de_ novo drug design is embodied in the discovery that individuals
predisposed to lupus erythematosus are slow genetic acetylators. Pre-acetylation
of various amines, or trial of non-acetylable compounds for anti-lupus activity
should limit the randomness in screening experiments (Reidenberg, 1980).
In most other cases, random screening has been the source of "lead" compounds
for further drug development. To be sure, these empirical searches have been
limited reasonably in the case of natural products by giving preference to those
with therapeutic folklore. In the case of synthetic substances, intuitive selec
tion has also played a role, choosing those that have some structural resemb
lance -feo compounds of known biological activity. Quantitative structure-
activity relationships may also be called in for help under special circumstances.
The time-honored search for "lead" compounds among natural products has
experienced a renaissance during the last quarter of a century although the yield
of therapeutically useful natural drugs has been low. Still, there is the lure
that both plant or microbial metabolites, and mammalian metabolites that play
a role in disease, have arisen from the same fundamental biochemicals which
occur in the oxidative cycles and other basic reactions. Thus the chances that
foreign natural products will have some relationship to disease-related
vertebrate metabolites are better than for synthetic chemicals without biochemical
analogy. In addition, the purely chemical interest in natural products, the out
guessing of Nature's reasons for biosynthesizing them in botanical and microbial
species, and the seductive voice of therapeutic folklore are incentives for
working in this field.
An activity very similar to natural products research is the structural elucida
tion and quantitation of drug metabolites in animal and human blood, tissues and
excreta. These studies not only shed light on metabolic activation and de-
activation of drugs but have to fulfill legal requirements concerning drug
metabolism before approval for the marketing of a drug is secured from
regulatory agencies.
Lead compounds from screening programs will continue to turn up among many classes
of compounds but this type of research is essentially chemically oriented and is
not based on biological considerations. Even the screening of antibiotics from
2
