Laughing Gas, Viagra, and Lipitor

Laughing Gas, Viagra, and Lipitor The Human Stories Behind the Drugs We Use Jie Jack Li 1 2006 3 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 © 2006 by Oxford University Press 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 Li, Jie Jack. Laughing gas, viagra, and lipitor : the human stories behind the drugs we use / Jie Jack Li. p. cm. Includes bibliographical references and index. ISBN-13 978-0-19-530099-4 ISBN 0-19-530099-8 1. Drugs—Miscellanea. 2. Nitrous oxide. 3. Sildenafil. I. Title. RM301.15.L5 2006 362.29'9—dc22 2006002586 987654321 Printed in the United States of America on acid-free paper foreword ny person interested in understanding the history of medical A progress and the way in which many of the most important medicines came into existence will be well rewarded by reading this latest book by Jie Jack Li, one of the most prolific and interesting authors in the field of molecular medicine and chemistry. And if that person happened to be aiming for or beginning a career in medicinal discovery, he or she would gain even more by so doing. The many case histories within this book contain a large number of valuable take-home lessons and extraordinary insights that have emerged from a spectrum of research over many years in medicinal science, or what can now be called molecular medicine. These stories reveal not only the complexity, unpredictability, and chal- lenges of the discovery process but also the intellectual and human qualities upon which success depended. I found this to be a most inspiring, engaging, and broadening reading experience, and I cannot imagine that this sense of reward would not be shared by most individuals who want to know more about health sciences, creativity, discovery, and just plain luck (good and bad). It is unimaginably difficult (and now very costly) to discover an important new therapeutic agent. Most people who have engaged in this effort for a lifetime have not been so fortunate. It is not easy to select a research objective that will turn out to be a winner. The enormous complexity of the human body (especially in molecular terms), the depth of our igno- rance in the molecular and biological sciences, and the lack of more pow- erful and yet to be discovered scientific research tools all conspire, like the fog of war, to obscure our vision in the search for a great new discovery. So one needs not only keen intellect and extraordinary personal qualities to be successful but also as much perspective, perception, and intuition as one can muster. This book provides a clear picture of these human elements behind success. As a bonus, it is also entertaining and enjoyable to read. It will be gratifying if the future audience for this fine work includes a wide swath of the general public, as they too will be fascinated by the in- ner workings of research at the frontier. E. J. Corey June 2005 Cambridge, Massachusetts Over the course of the past century, science has made such tremendous progress in the battle against human disease that many of the ailments that were lethal to our ancestors no longer pose a threat to us. Yet, for most people living in modern society, the process by which such a tremendous revolution has taken place remains a mystery, with drugs merely constitut- ing a pill or liquid prescribed by a doctor and bought at a pharmacy. Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We Use fills this gap beautifully. Through a series of enlightening and highly entertaining chapters, Jie Jack Li takes the reader on an unparalleled journey through the history of drugs, a trip that conveys both the science underlying the discovery and the personalities and drama that accompany them. Each section glows with behind-the-scenes glimpses at the brilliance, passion, and frailty of the people involved in the discoveries, from early pioneers to the heroic and landmark team efforts of today’s pharmaceutical companies that amalgamate the expertise of scientists in such diverse fields as synthetic chemistry, biology, pharmacokinetics, drug metabolism, and toxicology. What is particularly striking in chapter after chapter is the astonishing and sometimes chilling role that serendipity plays in the drug discovery process. For instance, how many people would have died from bacterial infec- tion had Fleming covered his petri dish while on vacation, or had the first in vivo studies of penicillin been performed on guinea pigs (as penicillin is toxic to them)? How many people know that the discovery of digitalis, used for the treatment of congenital heart failure, arose from a young lady’s love of flowers? These questions offer just a glimpse of the many hidden treasures that lie within this text. I offer my heartiest congratulations to Dr. Li for x foreword writing a uniquely original book that is a joy to read and that will un- doubtedly serve as an inspiration for scientists who are tirelessly at work developing the cures of the future and for students who aspire to such a noble cause. Phil S. Baran April 2005 La Jolla, California foreword xi preface his is a book on the history of drug discovery. More important, this is Ta book about drug discoverers that highlights their intellectual splen- dor, as well as their human frailty. Emil Fischer, perhaps the greatest or- ganic chemist ever, once stated: “Science is not an abstraction; but as a product of human endeavor it is inseparably bound up in its development with the personalities and fortunes of those who dedicate themselves to it.” In his book Ascent of Man, Jacob Bronowski wrote: “Discoveries are made by men, not merely by minds, so that they are alive and charged with indi- viduality.”1 When I set out to take on this project, I did not intend to write another scholarly tome—various topics have been published extensively in specialized areas of medical history. In contrast, I wanted to place emphasis on the human aspect of drug discovery by telling fascinating stories about the discoverers: their aspirations and activities, their hard work and frustra- tions, their hopes and fears, their setbacks and triumphs. History is replete with examples of breakthrough medicines that have saved millions of lives. The discovery of ether as an anesthetic by Morton, of penicillin as an an- tibiotic by Fleming, and of insulin for diabetes by Banting are just a few examples. The discoverers of these medicines are certainly benefactors to mankind—for instance, without penicillin, 75% of us probably would not be alive and reading this book, because some of our parents or grandparents would have succumbed to infections. On the other hand, as a testimony to human frailty, some of the scientists suffered misunderstanding, antipathy, and heartbreak. Some of them turned from collaborators into acrimonious scientific rivals. As is often the case, reality is more dramatic than fiction. I strongly believe that man, if given enough time, can overcome any medical problem. The future seemed seriously grim when AIDS became an epidemic 20 years ago. Now the advent of HIV protease inhibitors and reverse transcriptase inhibitors as antiviral agents have transformed AIDS from a death sentence to a disease that can be controlled. In preparing this manuscript, I have had the great fortune to communicate with some scientists who played pivotal roles in discover- ing the drugs we use. They are Steven J. Brickner and Michael R. Bar- bachyn (Zyvox); Carl Djerassi (norethindrone); V. Craig Jordan (Tamoxifen); Bruce D. Roth (Lipitor); Nicholas K. Terrett (Viagra); Joseph Vacca (Crixivan); Robert Vince (Ziagen), and Jürg Zimmermann (Gleevec). There have been many myths and inaccuracies associated with these well-known drugs. The inventors’ perspectives afford this book invaluable accuracy and insight, because history is not history un- less it is true. Drug discovery often involves many people across many disciplines— teamwork is of paramount importance. In this manuscript, I have often focused on the key players in the discovery of drugs. This is in no way meant to marginalize collaborations essential to the success of the venture. In preparing this manuscript, I have also incurred many debts of gratitude to my academic friends, E. J. Corey at Harvard University and Phil S. Baran at Scripps Research Institute, who have provided much en- thusiastic encouragement. Corey, a Nobel laureate in chemistry, read the entire manuscript and provided countless invaluable comments and suggestions. My friends in industry, Danielle Mills, Lorna H. Mitchell, Bruce D. Roth, and Dennis Vargo, also proofread the entire manuscript and offered numerous suggestions for improvements in terms of both science and English. Roth and Vargo, both veterans in the pharmaceutical industry, afforded precious insight into drug discovery. Friends and colleagues who also proofread portions of the manuscript are: Narendra Ambhaikar, Emily Andrews, Noah Burns, Michael DeMartino, Ben Hafensteiner, Douglas S.

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