Preface to the Second Edition Like the first edition of The Practice of Medicinal Chemistry medicinal chemistry,the measurement of biological activi es and the t phases of drug activity.This is fo nds including auto erence source for academic,as well as industrial,medicinal ing techniques,combinatorial chemistry and the use of the chemists.The general philosophy of the book is to complete interet,all of which serve to reduce pre-clinical develop- the cost of drugs.Further chapter (Prof uel J.Danishevsk and safa the com n of Studies in the chemistry and biology of the epothilones ics:molecular biology and X-ray crystallization to drug and eleutherobins,Conference given at the XXXIVemes discovery and development,including the design of pep- Inter ionales de Th6rapeutique, tidomimetic drugs:and the development of drug-delivery 0Juy.1998 ng org e allowed for the idntfication of a great umber of newtargets.corre legal and economic aspects of drug discovery and produc. sponding to hitherto unknown receptors or to new subtypes tion,including drug sources,good manufacturing practices. of already existing receptors.The massive use of combina drug nomenclature.patent the targets.The present challenge is to develop these hits into eration.for the time they spent writing their respective con usable and useful drug candidates.This book is,therefore. tributions and for their patience during the editing process. particularly timely as it covers abundantly the subject of Iam very grateful to Didier Rognan.Paola Ciapetti.Br nd p ck Ra expanded and refocused to reflect developments over the My thanks go also to the editorial staff of Academi nine years since the first edition was published.Experts Press in London.particularly to Margaret Macdonald and in the field have provided personal accounts of both tradi Jacqueline Read.Last but not least,I want to express my onal met s,and the newest ery and devel medicinal hemistry.usually only gained from years of practical experience. Camille G.Wermuth Like the previous edition,this edition includes a con cise introduction covering the definition and history of
Like the fi rst edition of The Practice of Medicinal Chemistry (nicknamed ‘The Bible’ by medicinal chemists) the second edition is intended primarily for organic chemists beginning a career in drug research. Furthermore, it is a valuable reference source for academic, as well as industrial, medicinal chemists. The general philosophy of the book is to complete the biological progress – Intellectualization at the level of function using the chemical progress Intellectualization at the level of structure (Professor Samuel J. Danishevsky, Studies in the chemistry and biology of the epothilones and eleutherobins, Conference given at the XXXIVémes Rencontres Internationales de Chimie Th6rapeutique, Facult6 de Pharmacie, Nantes, 8–10 July, 1998). The recent results from genomic research have allowed for the identifi cation of a great number of new targets, corresponding to hitherto unknown receptors or to new subtypes of already existing receptors. The massive use of combinatorial chemistry, associated with high throughput screening technologies, has identifi ed thousands of hits for these targets. The present challenge is to develop these hits into usable and useful drug candidates. This book is, therefore, particularly timely as it covers abundantly the subject of drug optimization. The new edition of the book has been updated, expanded and refocused to refl ect developments over the nine years since the fi rst edition was published. Experts in the fi eld have provided personal accounts of both traditional methodologies, and the newest discovery and development technologies, giving us an insight into diverse aspects of medicinal chemistry, usually only gained from years of practical experience. Like the previous edition, this edition includes a concise introduction covering the defi nition and history of medicinal chemistry, the measurement of biological activities and the three main phases of drug activity. This is followed by detailed discussions on the discovery of new lead compounds including automated, high throughput screening techniques, combinatorial chemistry and the use of the internet, all of which serve to reduce pre-clinical development times and, thus, the cost of drugs. Further chapters discuss the optimization of lead compounds in terms of potency, selectivity, and safety; the contribution of genomics; molecular biology and X-ray crystallization to drug discovery and development, including the design of peptidomimetic drugs; and the development of drug-delivery systems, including organ targeting and the preparation of pharmaceutically acceptable salts. The fi nal section covers legal and economic aspects of drug discovery and production, including drug sources, good manufacturing practices, drug nomenclature, patent protection, social-economic implications and the future of the pharmaceutical industry. I am deeply indebted to all co-authors for their cooperation, for the time they spent writing their respective contributions and for their patience during the editing process. I am very grateful to Didier Rognan, Paola Ciapetti, Bruno Giethlen, Annie Marcincal, Marie-Louise Jung, Jean-Marie Contreras and Patrick Bazzini for their helpful comments. My thanks go also to the editorial staff of Academic Press in London, particularly to Margaret Macdonald and Jacqueline Read. Last but not least, I want to express my gratitude to my wife Renée for all her encouragements and for her comprehensiveness. Camille G. Wermuth Preface to the Second Edition PRE-P374194.indd xxxvii RE-P374194.indd xxxvii 5/30/2008 9:13:33 PM /30/2008 9:13:33 PM
Preface to the Third Edition a unique volume It provides a practical overview of the ing the curiosity to read the preface.I cannot resist giv daily problems facing medicinal chemists,from the con- ing them some advice for doing good science. ception of new molecules through to the production of new First of all,be open-minded and original.As This derful illustration is found in Peter Hesse's cartoon below. informatics.More than 50 experts in the field from eight who technologies,providing readers with an insight into medic- inal chemistry. ho change in one of the eight sections of the book.I warmes the r)to Waterbeemd. "IT'S CALLED FIRE.IT RECYCLES WOOD." the thus ren suffering patients.Like many scientists.medicinal chem rial development of the book.Taking into account that we had to work with a cohc rof about 50authors,ea of then side they should avoid doing on the oth indebted to my assistant Odile Blin for the way she had Third,convinced as they may be that the neighbors mastered,efficiently and with friendliness,all the secretarial grass is always greener,they may be attracted to start their ularly the contacts with the different t. it on all their encouragements and for sacrificing many hours of inal chemist can do is to prepare a me-too of an inactive family life ino compound! Camille G.Wermuth
Like the preceding editions of this book, this third edition treats of the essential elements of medicinal chemistry in a unique volume. It provides a practical overview of the daily problems facing medicinal chemists, from the conception of new molecules through to the production of new drugs and their legal/economic implications. This edition has been updated, expanded and refocused to refl ect developments in the past 5 years, including 11 new chapters on topics such as hit identifi cation methodologies and cheminformatics. More than 50 experts in the fi eld from eight different countries, who have benefi ted from years of practical experience, give personal accounts of both traditional methodologies and the newest discovery and development technologies, providing readers with an insight into medicinal chemistry. A major change in comparison to the previous editions was the decision to alleviate my editorial burden in sharing it with seven section editors, each being responsible for one of the eight sections of the book. I highly appreciated their positive and effi cacious collaboration and express them my warmest thanks (in the alphabetical order) to Michael Bowker, Hugo Kubinyi, John Proudfood, Bryan Reuben, Richard Silverman, David Triggle and Han van de Waterbeemd. Another change was the decision taken by Elsevier/ Academic Press to publish the book in full colors thus rendering it more pleasant and user-friendly. I take this occasion to thank Keri Witman, Pat Gonzales, Kirsten Funk and Renske van Dijk for having successively ensured the editorial development of the book. Taking into account that we had to work with a cohort of about 50 authors, each of them having his personality, his original approach and his main busy professional live, this was not an easy task. I am deeply indebted to my assistant Odile Blin for the way she had mastered, effi ciently and with friendliness, all the secretarial work and particularly the contacts with the different authors and with the Elsevier development editors. As for the earlier editions, I also want to express my gratitude to my wife Renée and my daughters Delphine, Joëlle and Séverine for all their encouragements and for sacrifi cing many hours of family life in order to leave me enough free time to edit this new version of the “ Medicinal Chemist’s Bible. ” My fi nal thoughts go to the future readers of the book, and especially to the newcomers in Medicinal Chemistry having the curiosity to read the preface. I cannot resist giving them some advice for doing good science. First of all, be open-minded and original. As Schopenhauer noted, the task of the creative mind is “ not so much to see what no one has seen yet; but to think what nobody has thought yet, about what everyone sees. ” A wonderful illustration is found in Peter Hesse’s cartoon below. Preface to the Third Edition Second, always keep in mind that the object of Medicinal Chemistry is to synthetize new drugs useful for suffering patients. Like many scientists, medicinal chemists, have to navigate between two tempting reefs. On one side they should avoid doing “ NAAR ” : non-applicable applied research, on the other side they may be attracted by “ NFBR ” : non-fundamental basic search. ” Third, convinced as they may be that the neighbors grass is always greener, they may be attracted to start their research in using as a hit a recently published competitor’s product. In fact, the published compound may exhibit only a weak activity, therefore be very careful when starting a new program and never forget that the worst thing a medicinal chemist can do is to prepare a me-too of an inactive compound! Camille G. Wermuth PRE-P374194.indd xxxix RE-P374194.indd xxxix 5/30/2008 9:13:33 PM /30/2008 9:13:33 PM
Part I General Aspects of Medicinal Chemistry Hugo Kubinyi Section Editor
1 Part I General Aspects of Medicinal Chemistry Hugo Kubinyi Section Editor Ch01-P374194.indd 1 h01-P374194.indd 1 5/29/2008 5:41:54 PM /29/2008 5:41:54 PM
Chapter 1 A History of Drug Discovery From first steps of chemistry to achievements in molecular pharmacology Francois Chast I.INTRODUCTION C.Fight against microbes and rugs of the mind B.The N D.D RECENT TRENDS IN DRUG DISCOVERY biology fight against cancer A.From genetics to DNA n. An Hopes and limits for drug ellers and controversies REFERENCES B.Giving back the heart its youth receptors m dans desnpiclmodfent bereusmeni lespedply c Claude Bemard' During more than 2.000 vears.Hippocratic medical tradi "Ancients.Numerous drugs,most of them being prepared tion weighed on the development of a modern medicine with plant extracts,(Figure 1.1)sometimes efficacious,were ble.But none of them could respond to a chemical thes fo fwhat we call todaya drug.except drugs com sisting in sanguine,melancholic.phlegmatic and choleric The technology of making drugs was crude at best: Health and disease were seen as a question of balance or tinctures,poultice soups,and infusions were made with or alcohol-based extracts of freshly ground or to medicine and a maior medical advance was the founding of many hospitals and university medical schools. The objective of this first chapter istooffer a presentation of the fabulous history of drug discoveries,from traditiona ence,guided by traditional pharmacy emerged from ethnopharmacy,till the recen Copyright08.Elsevier Ld eh's The Practice of Medicinal Chemisiry 3 All rights reserved
3 Copyright © 2008, Elsevier Ltd Wermuth’s The Practice of Medicinal Chemistry All rights reserved. Chapter 1 During more than 2,000 years, Hippocratic medical tradition weighed on the development of a modern medicine and a renewed approach of the treatment of diseases. The basis for the use of drugs remained founded on empirical theories linked to the equilibrium of body’s “ humors ” consisting in sanguine, melancholic, phlegmatic and choleric. Health and disease were seen as a question of balance or imbalance with foods and herbs classifi ed according to their ability to affect natural homeostasis. Later, during the Middle Ages, Muslim world made signifi cant contributions to medicine and a major medical advance was the founding of many hospitals and university medical schools. Before the 1800s, pharmacy remained an empiric science, guided by traditional medicine, inherited from “ Ancients. ” Numerous drugs, most of them being prepared with plant extracts, ( Figure 1.1 ) sometimes effi cacious, were available. But none of them could respond to a chemical defi nition of what we call today a drug, except drugs coming from mineral reign. The technology of making drugs was crude at best: tinctures, poultices, soups, and infusions were made with water- or alcohol-based extracts of freshly ground or dried herbs or animal products such as bone, fat, or even pearls, and sometimes from minerals best left in the ground. 1 The objective of this fi rst chapter is to offer a presentation of the fabulous history of drug discoveries, from traditional pharmacy emerged from ethnopharmacy, till the recent I. INTRODUCTION A. The renewal of chemistry B. The dawn of the organic chemistry crosses the birth of biology II. TWO HUNDRED YEARS OF DRUG DISCOVERIES A. Pain killers: best-sellers and controversies B. Giving back the heart its youth C. Fight against microbes and viruses D. Drugs for immunosuppression E. Contribution of chemists to the fi ght against cancer F. Drugs for endocrine disorders G. Anti-acid drugs H. Lipid lowering drugs I. From neurotransmitters to receptors J. Drugs of the mind III. CONSIDERATIONS ON RECENT TRENDS IN DRUG DISCOVERY A. From genetics to DNA technology B. Hopes and limits for drug hunting REFERENCES Le médicament place l’organisme dans des conditions particulières qui en modifi ent heureusement les procédés physiques et chimiques lorsqu’ils ont été troublés. Claude Bernard * A History of Drug Discovery From fi rst steps of chemistry to achievements in molecular pharmacology François Chast * Leçons sur les Effets de Substances Médicamenteuses et Toxiques (1857) deuxième leçon (5 mars 1856), p.38: “ Drugs place the body in particular conditions which modify fortunately the physical and chemical processes when they have been disturbed. ” Ch01-P374194.indd 3 h01-P374194.indd 3 5/29/2008 5:41:54 PM /29/2008 5:41:54 PM
14 CHAPTER I A History of Drug Discovery experimental methodology.By formulating the principle of the conservation of mass.he gave a clea mng so concepts in chemistry Those scier tions would have their own impact on other developments in industrial and then medicinal chemistry.At the turn of the approach,drugs are 17851 ared sodium hydroxide(1789)and then,bleach (1796) and anhydrides.Louis Jacques Thenard prepared hydroger Antoine erome Bal d discovere due to the mastery of chemical or hysico-chem s This omp I the the 19 ing the FIGURE 1.atex owingou of poppy nard and Louis Pasteur. Beside oduction and development Rudolph Virchow, al tr ry, Of course.it is not possible to describe exhaustively.in Thus such a short chapter,such a complex and diversified his clinical or fundamental fields.After a period characterized ugs lants) more successful in treating or preventing diseases. d th h bio ogy (fe noloy)after rational research design and developmen I.INTRODUCTION in research laboratores Whereas the pur active m of A.The renewal of chemistry The 18th century concluded its progress in chemistry with cists toward performed in hat would be an enthusiastic environment.Jo Kingdom. in Sweder cal e ants.prog substances to the statute of chemical reagents.Scheele and ation processes.At the same time.the economical dimen Priestley prepared and studied oxygen.Both of them dis- sion of growing pharmaceutical industry transformed drug covered nitr ogen as a constituent of air,carbon monoxide s strategic ite mainly w it c interfe ewith mili ing taric.lactic.uric.p assic,citric,and gallic.Lavoisier is gen more often used by hysicians after the works of francoi erally considered as the founder of modern chemistry as Magendie (Figure 1.2)in France or Oscar Schmiedeberg creating the oxygen theory of combustion He should be dichot my took plac or the mo with as for their
4 CHAPTER 1 A History of Drug Discovery concepts of drug design, production and development, born from molecular genetics and molecular pharmacology. Of course, it is not possible to describe exhaustively, in such a short chapter, such a complex and diversifi ed history. We made the choice to describe the evolution of few families of drugs as examples of mankind ingenuity and intelligence to make pharmaceutical progress more and more successful in treating or preventing diseases. I. INTRODUCTION A . The renewal of chemistry The 18th century concluded its progress in chemistry with an enthusiastic environment. Joseph Priestley in the United Kingdom, Carl Wilhelm Scheele in Sweden, Antoine Laurent de Lavoisier in France, 2 gave a precise signifi cation to the chemical reactivity and promoted a large number of substances to the statute of chemical reagents. Scheele and Priestley prepared and studied oxygen. Both of them discovered nitrogen as a constituent of air, carbon monoxide, ammonia, and several other gases ; manganese, barium and chlorine; isolated glycerin and many acids, including tartaric, lactic, uric, prussic, citric, and gallic. Lavoisier is generally considered as the founder of modern chemistry as creating the oxygen theory of combustion. 3 He should be known as one of the most astonishing 18th century “ men of the Enlightenment, ” the founder of modern scientifi c experimental methodology. By formulating the principle of the conservation of mass, he gave a clear differentiation between elements and compounds, something so important for pharmaceutical chemistry. Few years later, Antoine François de Fourcroy, Louis Nicolas Vauquelin, Joseph Louis Proust, Jöns Jakob Berzelius, Louis-Joseph Gay-Lussac, and Humphrey Davy introduced new concepts in chemistry. Those scientists integrated the practical advancements of a new generation of experimenters. All these industrial innovations would have their own impact on other developments in industrial and then medicinal chemistry. 4 At the turn of the 19th century, as the result of a scientifi c approach, drugs are becoming an industrial item. Claude Louis Berthollet began the industrial exploitation of chlorine (1785). Nicolas Leblanc prepared sodium hydroxide (1789) and then, bleach (1796). Davy performed electrolysis and distinguished between acids and anhydrides. Louis Jacques Thénard prepared hydrogen peroxide and Antoine Jérôme Balard discovered bromide (1826). The growing of therapeutic resources was mainly due to the mastery of chemical or physico-chemical principles proposed by Gay-Lussac and Justus Von Liebig. 5 This chemists ’ generation, by realizing all these discoveries, established the compost of the therapeutic discoveries of the 19th century. The constitution of chemistry as a scientifi c discipline found a new turn few decades later by crossing the road of biology which included revolutionary works of Claude Bernard, 6 Rudolph Virchow, 7 and Louis Pasteur. 8 Besides these fundamental sciences, physiology, biochemistry, or microbiology were becoming natural tributaries of the outbreak of pharmacology. Thus, rational treatments were about to be designed on the purpose of new knowledge in various clinical or fundamental fi elds. After a period characterized by extraction and purifi cation from natural materials (mainly plants), drugs would be synthesized in chemical factories or prepared through biotechnology (fermentation or gene technology) after a rational research, design and development in research laboratories. Whereas the purpose was to isolate active molecules from plants during the fi rst half of the 19th century, the birth of organic chemistry following charcoal and oil industries, progressively led chemists and pharmacists toward organic synthesis performed in what would be called “ laboratory ” a new concept created by this generation of scientists. Even when those laboratories hosted discoveries like active principles extracted from plants, progresses in drug compounding and packaging made irreversible industrialization processes. At the same time, the economical dimension of growing pharmaceutical industry transformed drugs as strategic items, mainly when it could interfere with military processes, for instance during colonial expeditions. The “ modern ” word “ pharmacology ” became more and more often used by physicians after the works of François Magendie ( Figure 1.2 ) in France or Oscar Schmiedeberg in Germany. Progressively a clear dichotomy took place between those two entities. Materia Medica considered drugs with a static and conservative view as for their FIGURE 1.1 Opium latex fl owing out of poppy. Ch01-P374194.indd 4 h01-P374194.indd 4 5/29/2008 5:41:54 PM /29/2008 5:41:54 PM