《药物化学》课程参考文献：《The Practice of Medicinal Chemistry》书籍PDF电子版（实用药物化学，第三版，Camille-Georges Wermuth，2008）.pdf_大学文库

Biography Camille-Georges Wermuth PhD, Prof. and Founder of Prestwick Chemical, was Professor of Organic Chemistry and Medicinal Chemistry at the Faculty of Pharmacy, Louis Pasteur University, Strasbourg, France from 1969 to 2002. He became interested in Medicinal Chemistry during his two years of military service in the French Navy at the “Centre d’Etudes Physio biologiques Appliquées à la Marine” in Toulon. During this time he worked under the supervision of Dr Henri Laborit, the scientist who invented artifi cial hibernation and discovered chlorpromazine. Professor Wermuths’ main research themes focus on the chemistry and the pharmacology of pyridazine derivatives. The 3-aminopyridazine pharmacophore, in particular, allowed him to accede to an impressive variety of biological activities, including antidepressant and anticonvulsant molecules; inhibitors of enzymes such as mono-amine-oxidases, phosphodiesterases and acetylcholinesterase; ligands for neuro-receptors: GABA-A receptor antagonists, serotonine 5-HT3 receptor antagonists, dopaminergic and muscarinic agonists. More recently, in collaboration with the scientists of the Sanofi Company, he developed potent antagonists of the 41 amino-acid neuropeptide CRF (corticotrophinreleasing factor) which regulates the release of ACTH and thus the synthesis of corticoids in the adrenal glands. Professor Wermuth has also, in collaboration with Professor Jean-Charles Schwartz and Doctor Pierre Sokoloff (INSERM, Paris), developed selective ligands of the newly discovered dopamine D3 receptor. After a three-year exploratory phase, this research has led to nanomolar partial agonists which may prove useful in the treatment of the cocaine-withdrawal syndrome. Besides about 300 scientifi c papers and about 80 patents, Professor Wermuth is co-author or editor of several books including; Pharmacologie Moléculaire, Masson & Cie, Paris; Médicaments Organiques de Synthèse, Masson & Cie, Paris; Medicinal Chemistry for the Twenty-fi rst Century, Blackwell Scientifi c Publications, Oxford; Trends in QSAR and Molecular Modeling, ESCOM, Leyden, two editions of The Practice of Medicinal Chemistry, Academic Press, London and The Handbook of Pharmaceutical Salts, Properties Selection and Use, Wiley-VCH. Professor Wermuth was awarded the Charles Mentzer Prize of the Société Française de Chimie Thérapeutique in 1984, the Léon Velluz Prize of the French Academy of Science in 1995, the Prix de l’Ordre des Pharmaciens 1998 by the French Academy of Pharmacy and the Carl Mannich Prize of the German Pharmaceutical Society in 2000. He is Corresponding Member of the German Pharmaceutical Society and was nominated Commandeur des Palmes Académiques in 1995. He has been President of the Medicinal Chemistry Section of the International Union of Pure and Applied Chemistry (IUPAC) from 1988 to 1992 and from January 1998 to January 2000 was President of the IUPAC Division on Chemistry and Human Health. BIO-P374194.indd xxv IO-P374194.indd xxv 5/30/2008 9:49:52 PM /30/2008 9:49:52 PM

Michael J. Bowker studied chemistry and received his doctorate in Organic Chemistry from the University of Leeds, UK. After 5 years working for a multinational polymer company, he moved to May & Baker Ltd., a UK subsidiary of RhônePoulenc Santé (now Sanofi - Aventis). He was a Director of Analytical Chemistry for about 15 years and, more recently, Director of Preformulation at Aventis Pharma Ltd. He has been intimately involved in preformulation and solid-state activities, on a worldwide basis for more than 15 years. He has published several research papers and one chapter for a book on pharmaceutical salts and is currently a Director of M. J. Bowker Consulting Limited, a small company undertaking consultancy in salt selection, polymorph selection and pharmaceutical preformulation. Hugo Kubinyi is a Medicinal Chemist with 35 years of industrial experience in drug design, molecular modeling, protein crystallography and combinatorial chemistry, in Knoll and BASF AG, Ludwigshafen. He is a Professor of Pharmaceutical Chemistry at the University of Heidelberg, former Chair of The QSAR and Modelling Society and IUPAC Fellow. From his scientifi c work resulted more than 100 publications and seven books on QSAR, drug design, chemogenomics, and drug discovery technologies. John R. Proudfoot received his Ph.D. from University College Dublin, Ireland in 1981 working with Professor Dervilla Donnelly. He completed post doctoral studies with Professor Carl Djerassi at Stanford University and Professor John Cashman at the University of California San Francisco. In 1987, he joined Boehringer Ingelheim and is presently a Distinguished Scientist in the medicinal chemistry department. Bryan G. Reuben is Professor Emeritus of Chemical Technology at London South Bank University. He has written widely on the technology and economics of the chemical and pharmaceutical industries. His most recent experimental work was on hydrogen–deuterium exchange in protonated peptides and on the downstream processing of nisin. Richard B. Silverman is the John Evans Professor of Chemistry at Northwestern University. He has published 240 research articles, holds 38 domestic and foreign patents, has written four books, and is the inventor of Lyrica TM (pregabalin), marketed worldwide by Pfi zer for refractory epilepsy, neuropathic pain, fi bromyalgia, and (in Europe) for generalized anxiety disorder. David J. Triggle is a SUNY Disinguished Professor and the University Professor State University of New York at Buffalo. Educated in United Kingdom and Canada in physical and organic chemistry he has served a variety roles at Buffalo including Dean of the School of Pharmacy and University Provost. His work has been principally in the area of the chemical pharmacology of drug–receptor and drug–ion channel interactions. He is the author and editor of some 30 books and several hundred publications. Han van de Waterbeemd studied organic and medicinal chemistry and got his PhD at the University of Leiden. After his academic years at the University of Lausanne with Bernard Testa he worked for 20 years in the pharmaceutical industry for Roche, Pfi zer and AstraZeneca. His research interests are in optimizing compound quality using measured and predicted physicochemical and DMPK properties. He contributed to 145 research papers and book chapters, and (co-)edited 13 books. Section Editors BIO-P374194.indd xxvii IO-P374194.indd xxvii 5/30/2008 9:49:53 PM /30/2008 9:49:53 PM

xxx Contributors Ji-Cui Dong International Nonproprietary Names Programme Quality Assurance & Safety: Medicines World Health Organization 20, av. Appia CH-1211, Geneva 27 Bernard Faller Novartis Pharma AG Werk Klybeck Klybeckstrasse 141 WKL-122.P.33 CH-4057 Basel Switzerland Bennett T. Farmer Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road P.O. Box 368 Ridgefi eld, CT 06877 USA Bruno Galli Novartis Pharma AG TRD-PTM WSJ-340-451 Lichtstrasse 35 CH-4056 Basel Switzerland Jean-Pierre Gies Université Louis Pasteur Faculté de Pharmacie Equipe de Signalisation Cellulaire 74, Route du Rhin 67401 Illkirch-Cedex, France Bruno Giethlen Prestwick Chemical Inc. Boulevard Gonthier d’Andernach 67400 Illkirch France Fumitoshi Hirayama Faculty of Pharmaceutical Sciences Sojo University 4-22-1 Ikeda Kumamoto 860-0082 Japan Adrian N. Hobden Myriad Genetics, Inc. 320 Wakara Way Salt Lake City, UT 84108 USA Andrew L. Hopkins Division of Biological Chemistry and Drug Discovery College of Life Sciences University of Dundee Dundee Scotland DD1 5EH UK Peter Imming Institut für Pharmazie Martin-Luther-Universitaet Halle-wittenberg WolfgangLangenbeck-Str. 4 06120 Halle (Saale) Germany Paul F. Jackson Johnson & Johnson Pharmaceutical R & D, L.L.C. Welsh McKean Roads P.O. Box 776 Spring House, PA 19477 USA David G. I. Kingston Virginia Polytechnic Institute & State University Department of Chemistry, M/C 0212 3111 Hahn Hall West Campus Drive Blacksburg, VA 24061 USA Sabine Kopp Medicines Quality Assurance Programme Quality Assurance & Safety: Medicines World Health Organization 20, av. Appia CH-1211 Geneva 27 Hugo Kubinyi Donnersbergstrasse 9 67256 Weisenheim am Sand Germany Kamal Kumar Max Planck Institute of Molecular Physiology Otto-Hahn-Str. 11 D-44227 Dortmund Germany Yves Landry Université Louis Pasteur Faculté de Pharmacie Equipe de Signalisation Cellulaire 74, Route du Rhin 67401 Illkirch-Cedex, France CTR-P374194.indd xxx TR-P374194.indd xxx 5/30/2008 9:13:17 PM /30/2008 9:13:17 PM

Preface to the First Edition in the manufacture deals with the doubtful,however.whether chemists have been properly single volume.all the disparate bits of information which trained to design and synthesize new drugs or other bioac medicinal chemists gather over a career,and generally tive compounds.The majority of medicinal chemists work hare by w rd-of-mouth with their coll but whic istry who have to acquire the specific aspects of medicinal conversely,the most recent discovery and development ns bo K Is prec echnologie are presente 0 by specialists background sub of ject matter.such as the definition and history of medicinal hemistry.the me the phases c second par sts ente g into pharmac me s the most nal ch the risk of a certain lack of cohesiveness and of some over. ugh laps.especially as each chapter is written as an autonomic piece o infon Suc on was ant pro cepted ra first editi the optimization of the lead in terms of potency selectivity many of them are heavywei hts in medicinal chemistry and safery.In 'Primary Exploration of Structure-Activity In editing the book I have tried to ensure a balanced content Re ationships alle mo ope ind a m re-or-les consist style.H are tha ing the functions'deals with the rapid and systematic optimiza- a plurality of c inions and to pn sent and discuss a giver Spatial Organization.Receptor topic from different angles.Such as it is.this first edition considers the three can still improved and I am gratefuli n ad ance to all col leagues I ns fo an of he gonist transition and in general each com cribed has been identi- Parts VI and VII concentrate on the definition of satisfac fied by at least one reference.For compounds for which no tory drug-delivery the ature indication is given.the reader is referred molecu organ to the Me suitable water engraving designed for me by the late Charles (of utmost importance in medical practice)and improving who was my secondary school chemistry organoleptic properties (and thus rendering th drug admin eacher in M ulhouse.It represents an extract of Brueghel ent). lopmen an imn almost wholly self ch oil plan taught following their entry into industry. (Ricinus communis L.Euphorbiacede).which was the This book fills a gap in the available bibliography arting ont of the pyridazine chemistry in my laboratory. There is not.to the The his events any

Preface to the First Edition The role of chemistry in the manufacture of new drugs, and also of cosmetics and agrochemicals, is essential. It is doubtful, however, whether chemists have been properly trained to design and synthesize new drugs or other bioactive compounds. The majority of medicinal chemists working in the pharmaceutical industry are organic synthetic chemists with little or no background in medicinal chemistry who have to acquire the specifi c aspects of medicinal chemistry during their early years in the pharmaceutical industry. This book is precisely aimed to be their ‘bedside book’ at the beginning of their career. After a concise introduction covering background subject matter, such as the defi nition and history of medicinal chemistry, the measurement of biological activities and the three main phases of drug activity, the second part of the book discusses the most appropriate approach to fi nding a new lead compound or an original working hypothesis. This most uncertain stage in the development of a new drug is nowadays characterized by high-throughput screening methods, synthesis of combinatorial libraries, data base mining and a return to natural product screening. The core of the book (Parts III to V) considers the optimization of the lead in terms of potency, selectivity, and safety. In ‘Primary Exploration of Structure-Activity Relationships’, the most common operational stratagems are discussed, allowing identifi cation of the portions of the molecule that are important for potency. ‘Substituents and functions’ deals with the rapid and systematic optimization of the lead compound. ‘Spatial Organization, Receptor Mapping and Molecular Modelling’ considers the threedimensional aspects of drug-receptor interactions, giving particular emphasis to the design of peptidomimetic drugs and to the control of the agonist- antagonist transition. Parts VI and VII concentrate on the defi nition of satisfactory drug-delivery conditions, i.e. means to ensure that the molecule reaches its target organ. Pharmacokinetic properties are improved through adequate chemical modifi cations, notably prodrug design, obtaining suitable water solubility (of utmost importance in medical practice) and improving organoleptic properties (and thus rendering the drug administration acceptable to the patient). Part VIII, ‘Development of New Drugs: Legal and Economic Aspects’, constitutes an important area in which chemists are almost wholly self taught following their entry into industry. This book fi lls a gap in the available bibliography of medicinal chemistry texts. There is not, to the authoreditor’s knowledge, any other current work in print which deals with the practical aspects of medicinal chemistry, from conception of molecules to their marketing. In this single volume, all the disparate bits of information which medicinal chemists gather over a career, and generally share by word-of-mouth with their colleagues, but which have never been organized and presented in coherent form in print, are brought together. Traditional approaches are not neglected and are illustrated by modern examples and, conversely, the most recent discovery and development technologies are presented and discussed by specialists. Therefore, The Practice of Medicinal Chemistry is exactly the type of book to be recommended as a text or as fi rst reading to a synthetic chemist beginning a career in medicinal chemistry. And, even if primarily aimed at organic chemists entering into pharmaceutical research, all medicinal chemists will derive a great deal from reading the book. The involvement of a large number of authors presents the risk of a certain lack of cohesiveness and of some overlaps, especially as each chapter is written as an autonomic piece of information. Such a situation was anticipated and accepted, especially for a fi rst edition. It can be defended because each contributor is an expert in his/her fi eld and many of them are ‘heavyweights’ in medicinal chemistry. In editing the book I have tried to ensure a balanced content and a more-or-less consistent style. However, the temptation to infl uence the personal views of the authors has been resisted. On the contrary, my objective was to combine a plurality of opinions, and to present and discuss a given topic from different angles. Such as it is, this fi rst edition can still be improved and I am grateful in advance to all colleagues for comments and suggestions for future editions. Special care has been taken to give complete references and, in general, each compound described has been identi- fi ed by at least one reference. For compounds for which no specifi c literature indication is given, the reader is referred to the Merck Index. The cover picture of the book is a reproduction of a copperplate engraving designed for me by the late Charles Gutknecht, who was my secondary school chemistry teacher in Mulhouse. It represents an extract of Brueghel’s engraving The alchemist ruining his family in pursuing his chimera, surmounted by the aquarius symbol. Represented on the left-hand side is my lucky charm caster oil plant (Ricinus communis L., Euphorbiaceae), which was the starting point of the pyridazine chemistry in my laboratory. The historical cascade of events was as follows: cracking of caster oil produces n-heptanal and aldolization of PRE-P374194.indd xxxv RE-P374194.indd xxxv 5/30/2008 9:13:33 PM /30/2008 9:13:33 PM