________________________________________________________________________________________________________________________ ______________________________ Drug Discovery A History Walter Sneader School of Pharmacy University of Strathclyde, Glasgow, UK ________________________________________________________________________________________________________________________ ______________________________ Drug Discovery ________________________________________________________________________________________________________________________ ______________________________ Drug Discovery A History Walter Sneader School of Pharmacy University of Strathclyde, Glasgow, UK Copyright u 2005 John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England Telephone (+44) 1243 779777 Email (for orders and customer service enquiries): [email protected] All Rights Reserved. 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Library of Congress Cataloging-in-Publication Data Sneader, Walter Drug discovery : a history / Walter Sneader. p. ; cm. Includes bibliographical references and index. ISBN-10 0-471-89979-8 (hardback : alk. paper) – ISBN-10 0-471-89980-1 (pbk. : alk. paper) ISBN-13 978-0-471-89979-2 (HB) 978-0-471-89980-8 (PB) 1. Pharmacy–History. 2. Drug development–History. 3. Pharmacognosy–History. I. Title [DNLM: 1. Pharmaceutical Preparations–history. QV 11.1 S671da2005] RS61.S637 2005 615’.19’90–dc22 2005041804 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN-13 978-0-471-89979-2 (HB) 978-0-471-89980-8 (PB) ISBN-10 0-471-89979-8 (HB) 0-471-89980-1 (PB) Typeset by Dobbie Typesetting Ltd, Tavistock, Devon Printed and bound in Great Britain by Antony Rowe Ltd, Chippenham, Wiltshire This book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production. ________________________________________________________________________________________________________________________ ______________________________ Dedication The quest for the elixir of life by the mediaeval alchemists may not have resulted in success, but the last one hundred years have witnessed the introduction of a number of drugs that have literally saved countless millions of lives. Society at large is indebted to the men and women in the laboratories and clinics of the pharmaceutical industry, research institutes, hospitals and universities whose commitment to science has brought about what in an earlier era would simply have been called miracles. This book is dedicated to these men and women. ________________________________________________________________________________________________________________________ ______________________________ Contents Preface ix Foreword xi Chapter 1 Introduction 1 PART 1 LEGACY OF THE PAST Chapter 2 The Prehistoric Period 8 Chapter 3 Pre-Hellenic Civilisations 12 Chapter 4 Greece and Rome 18 Chapter 5 The Arab World 24 Chapter 6 Herbals 32 Chapter 7 Chemical Medicines 41 Chapter 8 Systematic Medicine 74 PART 2 DRUGS FROM NATURALLY OCCURRING PROTOTYPES SECTION I PHYTOCHEMICALS Chapter 9 Alkaloids 88 Chapter 10 Non-Alkaloidal Plant Products 106 Chapter 11 Plant Product Analogues and Compounds Derived from Them 115 SECTION II BIOCHEMICALS Chapter 12 The Origins of Hormone Therapy 151 Chapter 13 Neurohormones 155 Chapter 14 Peptide Hormones 164 Chapter 15 Sex Hormones 173 viii _____________________________________________________________________________________________________ Contents Chapter 16 Adrenal Cortex Hormones 179 Chapter 17 Prostaglandins 185 Chapter 18 Hormone Analogues 188 Chapter 19 Vitamins 226 Chapter 20 Antimetabolites 248 Chapter 21 Blood and Biological Products 269 SECTION III DRUGS FROM MICRO-ORGANISMS Chapter 22 Antibiotics 287 Chapter 23 Antibiotic Analogues 319 Chapter 24 Pharmacodynamic Agents from Micro-organisms 341 Chapter 25 Analogues of Pharmacodynamic Agents from Fungi 349 PART 3 SYNTHETIC DRUGS Chapter 26 The First Synthetic Drugs and Their Analogues 355 Chapter 27 Drugs Originating from the Screening of Dyes 375 Chapter 28 Drugs Originating from the Screening of Organic Chemicals 403 Chapter 29 Drugs Discovered through Serendipitous Observations Involving Humans 432 Chapter 30 Drugs Discovered through Serendipity in the Laboratory 438 Chapter 31 Concluding Remarks 446 Index 448 ________________________________________________________________________________________________________________________ ______________________________ Preface The contents of this book range from the faltering attempts of our ancient ancestors to discover herbal remedies to the present quest of scientists to develop safe, efficacious medicines. This will enable readers to understand both why efficacious drugs were not developed until the twentieth century and why progress has been so rapid over the past fifty years. The book consists of three parts. The first part progresses from the possible use of medicinal herbs by Neanderthals on to the endeavours of ancient civilisations in Mesopotamia, Egypt, Greece and Rome. A subsequent consideration of the impact of Greek medicine on the Arab world and then renaissance Europe is followed by an examination of the heritage of the alchemists whose attempts to transmute base metals into gold provided the chemical techniques that allowed purified metallic compounds to be introduced into medicine. After reviewing how the influence of the enlightenment on drug discovery was impeded by the introduction of unsubstantiated medical systems that were popular from the seventeenth to nineteenth centuries, this part of the book concludes with an account of the twentieth century development of life-saving organic compounds incorporating various metals. The second part of the book examines the commonest source of drug prototypes from which other medicines are derived – the natural world. Prototypes from vegetable, animal and microbial sources are described in separate chapters, as are the medicinal compounds prepared from them. The problem of relying on nature as a source of drug prototypes is confronted. Modern drug discovery has consisted of a series of thematic developments that began with the isolation of pure alkaloids and glycosides from plants in the early years of the nineteenth century. One hundred years later, a parallel development witnessed the isolation of pure hormones from mammalian sources. The chapters throughout the book are organised so as to heighten awareness of such thematic developments, but this is particularly relevant in the second part of the book. The third part considers those synthetic compounds that have served as drug prototypes, followed by a consideration of compounds derived from them. The role of serendipity in providing synthetic prototypes is also investigated. The book ends with a cautionary note concerning the future of drug discovery. The specialist reader will find that the book contains an extensive list of bibliographic references relating to the discovery of drugs, but the book has been written for the general reader. No particular expertise in chemistry is assumed, but chemical structures have been interspersed with the text to enable those familiar with the subject to obtain a deeper understanding. Their presence should also enable others to begin to appreciate why chemistry has appealed to so many great minds. The chemical structures are presented in such a way as to allow even those with little experience of the subject to understand how prototypes and compounds obtained from them