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Medicinal Chemistry This page intentionally left blank Medicinal Chemistry A Molecular and Biochemical Approach THIRD EDITION Thomas Nogrady Donald F. Weaver 2005 Oxford University Press,Inc.,publishes works that further Oxford University’s objective of excellence in research,scholarship,and education. Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam Copyright © 1988,2005 by Oxford University Press,Inc. Published by Oxford University Press,Inc. 198 Madison Avenue,New York,New York 10016 www.oup.com Oxford is a registered trademark of Oxford University Press All rights reserved. No part of this publication may be reproduced, stored in a retrieval system,or transmitted,in any form or by any means, electronic,mechanical,photocopying,recording,or otherwise, without the prior permission of Oxford University Press. Library of Congress Cataloging-in-Publication Data Nogrady,Th. Medicinal chemistry:a molecular and biochemical approach/Thomas Nogrady,Donald F. Weaver—3rd ed. p. cm Includes bibliographical references and index ISBN 13 978-0-19510455-4; 978-0-19-510456-1 (pbk.) ISBN 0-19-510455-2; 0-19-510456-0 (pbk.) 1. Pharmaceutical chemistry. I. Weaver,Donald F.,1957-II. Title. [DNLM:1. Chemistry,Pharmaceutical. 2. Drug Design. 3. Receptors, Drug. QV 744 N777m 2005] RS403.N57 2005 615′.7—dc22 2004058105 9 8 7 6 5 4 3 2 1 Printed in the United States of America on acid-free paper To Heather and Cheryl Inspiration,Critic,Sustenance This page intentionally left blank Preface There have been many changes in medicinal chemistry and molecular pharmacology since the second edition of this book was published in 1988. Accordingly, it has required extensive updating. This process was initiated in the Chemistry Department of Queen’s University,Kingston,Canada where Dr. Nico van Gelder,an Adjunct Emeritus Professor,introduced the now retired Thomas Nogrady to Donald Weaver,a medicinal chemist and clinical neurologist. Together, Weaver and Nogrady undertook the chal- lenge of updating this book. In this way the third edition of Medicinal Chemistry was started and the two authors have worked together to ensure a continuity in the style and content that has made this book popular among students and researchers alike. The areas of change in this new edition are many and varied. Since molecular modeling has assumed an increasingly prominent role in drug discovery, we have expanded the discussion of modeling techniques. Description of other new techniques such as high throughput screening and applications of genomics in drug design have also been added. In terms of medicinal chemistry applications, neuropharmacology has enjoyed many advances in the past decade; much new information from this field has been included. In concert with these advances,new therapies have been introduced for Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and epilepsy – these new therapies are explicitly discussed in the third edition. Emerging disorders like those of protein folding (e.g. Creutzfeldt-Jakob disease and other prion disorders) are also considered. Chapter 5 on hormonal therapies has been thoroughly updated and re-organized. An entire new chapter on the immune system has been added (chapter 6),reflecting the increased interest in therapeutic molecular manipulation of immunity. Emerging enzyme targets in drug design (e.g. kinases,caspases) are discusses in this edition. Recent information on voltage-gated and ligand-gated ion channels has also been incorporated. The sections on antihypertensive, antiviral,antibacterial,anti-inflammatory,antiarrhythmic,and anti-cancer agents,as well as treatments for hyperlipidemia and for peptic ulcer,have been substantially expanded. Despite these many changes, the overall structure and philosophy of the book remain unchaged. Therapeutic agents are organized according to their targets – the conceptual vii viii MEDICINAL CHEMISTRY centerpiece of the first two editions. The nine chapters of the third edition are grouped in two parts: the basic principles of medicinal chemistry (chapters 1–3), and applications of medicinal chemistry from a target-centered viewpoint (chapters 4–9). Given this organizational structure, the book is not a catalogue of drugs. It does not present medicinal chemistry in a “telephone directory of drugs”way. Rather,it emphasizes the understanding of mechanisms of drug action, which includes drug and receptor structure. The book’s target-centered philosophy facilities a clear, mechanistic understanding of how and why drugs work. This should give students a conceptual framework that will enable them to continue learning about drugs and drug action long after they have left school. As with the first and second editions,this text is aimed primarily at students of pharmacy, pharmacology and chemistry who are interested in drug design and development. It provides the core of biochemical- and molecular-level thinking about drugs needed for a basic medicinal chemistry course. Another new feature of this edition is designed to enhance the book’s appeal to all readers:the multiple sections on the “Clinical–Molecular Interface.”These sections strengthen the book’s clinical relevance by making it easier to understand the treatment of human disease at a molecular level. Many co-workers, colleagues and reviewers have given their time, expertise and insights to aid the development of this third edition. Dr. Chris Barden (Department of Chemistry,Dalhousie University) provided detailed remarks on the entire book. Joshua Tracey checked molecular structures for accuracy,providing extensive assistance with molecular formulae; Vanessa Stephenson checked references and the suggested reading citations; and Dawnelda Wight provided clerical assistance with tables. Cheryl Weaver, Felix Meier,Vanessa Stephenson,Valerie Compagna-Slater,Michael Carter,Buhendwa Musole,Kathryn Tiedje,and Colin Weaver provided additional assistance with figures and diagrams. To all of them we offer our thanks. In addition,one of us (DFW) wishes to express his gratitude to Dr. R. A. Purdy,Head, Division of Clinical Neurology, Dalhousie University, for his generous “protection of time”to provide the many hours necessary for the revision of this book. We also thank the editorial staff of Oxford University Press, Jeffrey House in particular, and Edith Barry,for working on the second and third edition,and for their never-ending patience. As with previous editions, we look forward to a continuing dialogue with our readers so that future editions can be further improved. T. N. Kingston,Ontario D. F. W. Halifax,Nova Scotia April,2005 Contents I GENERAL MOLECULAR PRINCIPLES OF DRUG DESIGN Introduction to Part I 5 Drug Design:A Conceptual Approach 5 Drug Design:A Practical Approach 7 Drug Design:The Humanitarian Approach 8 1. Basic Principles of Drug Design I—Drug Molecules: Structure and Properties 9 1.1 Definition and Properties of a Drug Molecule 9 1.2 Physicochemical Properties of Drug Molecules 24 1.3 Shape (Geometric,Conformational,Topological,and Steric) Properties of Drug Molecules 32 1.4 Stereochemical Properties of Drug Molecules 36 1.5 Electronic Properties of Drug Molecules 40 1.6 Predicting the Properties of Drug Molecules: Quantum Mechanics and Molecular Mechanics 43 Selected References 63 2. Basic Principles of Drug Design II—Receptors: Structure and Properties 67 2.1 The Receptor Concept and its History 67 2.2 The Nature of Receptors and Criteria for Receptor Identity 68 2.3 Definitions of Drug–Receptor Binding Interactions 69 2.4 Definitions of Classical Binding Terms for Drug–Receptor Interactions 75 ix