THE PRACTICE OF MEDICINAL CHEMISTRY THIRD EDITION EDITED BY CAMILLE GEORGES WERMUTH
Biography t and thus the synthesis of corticoids in the adrenal glands PhD. Prof and Founder Professor Wermuth has also,in collaboration with Professor Prestwick Chemical lean-Charles Schwartz and Doctor Pierre Sokolof (INSERM,Pars) selective ligands of the the-year Louis tial agonists which may prove useful in the treatment of the University cocaine-withdrawal syndrome 013 Ma &Cie.Pari ing his two years of militar Medicaments Organiques de Synthese,Masson&Cie,Paris service in the French Navy at Medicinal Chemistry for the Twenty-first Century.Blackwell the"Centre d'Etudes Physic Trends in QSAR and Marine"in Toulon.During h Che supervision of Dr Henri Laborit,the scientist who invented artificial hibernation and discovered chlorpromazine Selection and Use.Wiley-VCH. Protessor Wermuths main research themes focus on Prote e 1984 allowed him to accede to an im riety of biologi Scie e in 1995,the Prix de I'Ordre des Phan ciens 1998 activities,including antidepre ant and anticonvulsant mole by the French Academy of Pharmacy and the Carl Mannich Prize of the German Pharmaceutical Society in 2000.He phosphodi teras Germ 5-HT3rec entor anta nists do and mu in 1905 He has heen President of the ago nists more recently in collaboration with the scientist Medicinal Chemistry Section of the International Union of of the Sanofi Company.he deve potent antagonists Pure and Applied Chemistry (IUPA C)from 1988 to 199 of the lent or the
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
Section Editors Michael J.Bowker studied Brvan G.Reuben is Professon hemistry received Emertus of Chemical lechn uth of Leeds UK.After 5 ye widely on the technology and vorking economics of the chemical and mpany. he e Hi Poulene Sante (now Sanofi- Aventis).He was a Directo tides and on the downstream Analytical Chemistry processing of nisin. ently Director of Pref about years and. 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 University.He has published 240 research articles,holds 38 D: a foreign pa salt selection,polymorph selection and pharmaceutical preformulation. by Pfizer for refractory epi Hugo Kubinyi is a Medicinal David J.Triggle is a SUNY molecular Disinguished Professor and protein crystallography State chem ated in In AG. an Kingdom and Canada in phy Professor of Pha ical and organic chemistry Chemistry at the University Chai ing Dean o of Heidelberg,former ot The QSA nd M n University Provost.His work 100 has been principally in the tions and seven books on QSAR.drug design,chemog. area of the chemical pharma enomics,and drug discovery technologies. Han van de Waterbeemd studied organic and medici nal che stry and got 1981 workin Professor Dervilla Donnelly University of lausanne with He completed post doc Testa he worked for udies with and Astrazeneca.Hisre Cashman at the University interests are in optimizing of California san francisco comp nd quality using meas 1987.he joine Boehringer Ingelheim and is pres red d predicted physi emistry chemical and DMPK 45
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
Contributors Raffaella.G.Balocco Mattavelli PO.Box12233.MD:B3-05 Manager of the International Nonproprietary Research Triangle Park,NC27709 Names Programme USA 20 av David Cavalla CH-1211,Geneva 27 Inc UK 320 Wakara Way Salt Lake City,UT84108 Francois Chast Pharmacy.Pharmacology.Toxicology Department USA Hotel-Die Patrick Bazzini Parvis Notre-Dame Prestwick Cher 75004Pni mical inc France boulevard gonthier Paola Ciapetti Head of Medicinal Chemistry Novalyst Discovery Frans M.Belpaire 0170 France Belgium e Con Koen Bou Boulevard Gonthier d'Andernach Laboratory of Medical Biochemistry and Clinical Analysis 67400 Illkirch Faculty of Pharmaceutical Sciences France Gent straat 72 Gordon M.Cragg Belgium 003w7h t Suite 206 MichaelI.Bowker Frederick.MD 21701 M.J.Bowker Consulting Ltd. USA 36.Burses Way Patrick M.Dansette Laboratoire de Chimie et Biochimie Pharmacol giq et Toxicologiques scartes n D.Brvant CNRS Medicinal Chemistry Group 45.Rue des Saints Peres Laboratory of Pharmacology and Chemistry F-75270 Paris Cedex 06 National Institute of Environmental Health Sciences France
Raffaella. G. Balocco Mattavelli Manager of the International Nonproprietary Names Programme Quality Assurance & Safety: Medicines World Health Organization 20, av. Appia CH-1211, Geneva 27 Paul L. Bartel Myriad Genetics, Inc. 320 Wakara Way Salt Lake City, UT 84108 USA Patrick Bazzini Prestwick Chemical Inc. Boulevard Gonthier d’Andernach 67400 Illkirch France Frans M. Belpaire Heymans Institute for Pharmacology Jeroom Duquesnoylaan 37 9051 Gent Belgium Koen Boussery Laboratory of Medical Biochemistry and Clinical Analysis Faculty of Pharmaceutical Sciences Gent University Harelbekestraat 72 9000 Gent Belgium Michael J. Bowker M.J. Bowker Consulting Ltd. 36, Burses Way Hutton, Brentwood Essex CM13 2PS UK Sharon D. Bryant Medicinal Chemistry Group Laboratory of Pharmacology and Chemistry National Institute of Environmental Health Sciences P.O. Box 12233, MD: B3-05 Research Triangle Park, NC 27709 USA David Cavalla Arachnova St. John’s Innovation Centre Cambridge CB4 4WS UK François Chast Pharmacy, Pharmacology, Toxicology Department Hôtel-Dieu 1, Place du Parvis Notre-Dame 75004 Paris France Paola Ciapetti Head of Medicinal Chemistry Novalyst Discovery Boulevard Sébastien Brant BP 30170 F-67405 Illkirch Cedex France Jean-Marie Contreras Prestwick Chemical Inc. Boulevard Gonthier d’Andernach 67400 Illkirch France Gordon M. Cragg Natural Products Branch National Cancer Institute 1003 W 7th Street, Suite 206 Frederick, MD 21701 USA Patrick M. Dansette Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques Université PARIS Descartes UMR 8601 – CNRS 45, Rue des Saints Pères F-75270 Paris Cedex 06 France Contributors CTR-P374194.indd xxix TR-P374194.indd xxix 5/30/2008 9:13:17 PM /30/2008 9:13:17 PM
Contributors Ji-Cui Dong Andrew L.Hopkins AS of Biological Chemistry and Drug Discovery 20.av ppia Dundee CH-1211.Geneva 27 land DDI E Bernard Faller Novartis Pharma AG Werk Klybeck e Ke22P.33 141 Martin-Luther-Universitaet Halle-wittenberg Wolfgang CH-4057 Basel Switzerland Paul E Iackson Johnson Johnson Rideebury Road Pharmaceuticals,Inc an Roads PO Box 368 PO.Box 776 eheld.C7 USA g House.PA 19477 ings Polyt eUniversity TRD-PTM WSJ-340-451 D of Chemistry.M/C021 e3 3111 Hahn Hall Jean-Pierre Gies Sabine Kopp aculte ion Cellulaire 74.Route du Rhin 67401 Illkirch-Cedex. rganization France CH-1211 Geneva 27 Hugo Kubinyi se 9 Boulevard Gonthier d'Andernach 67256 Weisenheim am Sand 67400 Illkirch Germany France Fumitoshi Hiravama titute of Molecular Physiology Faculty of Pharmaceutical Sciences Sojo Unive D-44227 Dortmund Germany 60.008 Japan Adrian N.Hobden Faculte de Pharmacie Myriad Genetics.Inc. Equipe de Signalisation Cellulaire 67401C USA france
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