Contributors Thie ns maria hofhauer-G6 2344 Maria enzersdorf 1003 w 7th Street.suite 206 Austria Innrain 52 6020 Innsbruck Austria 31,Avenue Paul Vaillant-Couturier Sophie Lasseur International Nonproprietary Names Programme :Medicines Alex Polinsky Research Technologie 0 Pfizer Glob earch and Developmen C Geneva 27 USA 10 Conshire i John R.Pro Wate rford.CT06385-4122 USA ticals Inc 900 Ridgebury Road UPS 831-Bat.11 CNRS Z.Rankovic Cedex Organon La France Andre Manr Lanarkshire Scotland ML1 5SH UK UMR 7175 LC 1 ULP/CNRS Allen B.Reitz Faculte de Pha Iohnson lohnson Dvlepem.LLC Welsh Christophe Morice Inc Bryan G.Reuben d'Andem ach London South Bank University 67400 Illkirch France UK atories Ltd. Jean-Michel Rondeau A part of the Schering Plough Corporation ovartis harma AC tutes for BioMedical Research Scotland ML1 5SH CH-4056 Basel UK Switzerland
Contributors xxxi Thierry Langer Inte:Ligand GmbH Clemens Maria Hofbauer-G.6 2344 Maria Enzersdorf Austria Institute of Pharmacy University of Innsbruck Innrain 52 6020 Innsbruck Austria Sophie Lasseur International Nonproprietary Names Programme Quality Assurance & Safety: Medicines World Health Organization 20, av. Appia CH-1211, Geneva 27 Christopher A. Lipinski Melior Discovery 10 Conshire Drive Waterford, CT 06385-4122 USA Anne-Christine Macherey Unité de Prévention du Risque Chimique UPS 831–Bat.11 CNRS Avenue de la Terrasse F-91198 Gif sur Yvette Cedex France André Mann Département de Pharmacochimie de la Communication Cellulaire UMR 7175 LC 1 ULP/CNRS Faculté de Pharmacie 74 route du Rhin 67401 Illkirch France Christophe Morice Prestwick Chemical Inc. Boulevard Gonthier d’Andernach 67400 Illkirch France Richard Morphy Organon Laboratories Ltd. A part of the Schering Plough Corporation Newhouse Lanarkshire Scotland ML1 5SH UK David J. Newman Natural Products Branch National Cancer Institute 1003 W 7th Street, Suite 206 Frederick, MD 21701 USA Jean-Pierre Nowicki Sanofi -Aventis RD 31, Avenue Paul Vaillant-Couturier 92220 Bagneux France Alex Polinsky Research Technologies Pfi zer Global Research and Development 620 Memorial Drive Cambridge, MA 02138 USA John R. Proudfoot Boehringer Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road P.O. Box 368 Ridgefi eld, CT 06877 USA Z. Rankovic Organon Laboratories Ltd. A part of the Schering Plough Corporation Newhouse Lanarkshire Scotland ML1 5SH UK Allen B. Reitz Johnson & Johnson Pharmaceutical Research and Development, LLC Welsh McKean Rds. Spring House, PA 19477 USA Bryan G. Reuben London South Bank University 24 Claverley Grove London N3 2DH UK Jean-Michel Rondeau Novartis Pharma AG Novartis Institutes for BioMedical Research WSJ-88.8.08A CH-4056 Basel Switzerland CTR-P374194.indd xxxi TR-P374194.indd xxxi 5/30/2008 9:13:17 PM /30/2008 9:13:17 PM
Contributors Sally Rose Maria Souleau Welwyn Garden ity france AL7 3AX P.Heinrich Stahl Bernard Scatton Sanofi-Aventis RD 79104 Freiburg im Breisgau Germany agneu France Bernard Testa Service de Pharmacie.CHUV al Inc Boulevard Gonthier Re011L sann d'Anderach Switzerland 67400 Illkirch France David J ofPharmaceutical Science rsity es ane 126 Cooke Hall Buffalo.NY 14260 avenue de l'observatoire USA 75006 Paris France Kaneto Uekama Herman Schreuder Faculty of Pharmaceutical Sciences Aventis Pharma Deutschland GmbH Kumamoto 860-0082 am Main Japan Johan Van de Voorde Ghent Univer Pharmaceutical R&D.L.L.C. Vascular Research Unit Welsh McKean Roads De Pintelaan 185-Blok B Richard B Han van de Waterbeemd LG DECS 2145.Sheridon Road Alderley Park.50S39 ompound Sciences o L020-3113 Macclesfield Wolfgang Sippl Department of Pharmaceutical Chemistry Herbert Waldmann Martin-Luther-Universitt Halle-Wittenberg Max Planck Institute of Molecular Physiology 06120 Haule (Saale eck-Str.4 Germany Germany
xxxii Contributors Sally Rose Cresset BioMolecular Discovery Ltd BioPark Hertfordshire Broadwater Road Welwyn Garden City Herts., AL7 3AX UK Bernard Scatton Sanofi -Aventis RD 31, Avenue Paul Vaillant-Couturier 92220 Bagneux France Laurent Schaeffer Prestwick Chemical Inc. Boulevard Gonthier d’Andernach 67400 Illkirch France Jean-Michel Scherrmann INSERM U 705; CNRS 7157 University Paris Descartes and Paris Diderot Department of Pharmacokinetics Faculty of Pharmacy 4, avenue de l’Observatoire 75006 Paris France Herman Schreuder Aventis Pharma Deutschland GmbH Building G 6865A D-65926 Frankfurt am Main Germany Brian C. Shook Johnson & Johnson Pharmaceutical R & D, L.L.C. Welsh McKean Roads P.O. Box 776 Spring House, PA 19477 USA Richard B. Silverman Department of Chemistry Northwestern University 2145, Sheridon Road Evanston, IL 60208-3113 USA Wolfgang Sippl Department of Pharmaceutical Chemistry Martin-Luther-Universität Halle-Wittenberg Wolfgang-Langenbeck-Str. 4 06120 Halle (Saale) Germany Maria Souleau Sanofi -Aventis 20, Rue Raymond Aron 92160 Antony France P. Heinrich Stahl Lerchenstrasse 28 79104 Freiburg im Breisgau Germany Bernard Testa Service de Pharmacie, CHUV Centre Hospitalier Universitaire Vaudois Rue du Bugnon 46 CH-1011 Lausanne Switzerland David J Triggle SUNY at Buffalo School of Pharmaceutical Sciences 126 Cooke Hall Buffalo , NY 14260 USA Kaneto Uekama Faculty of Pharmaceutical Sciences Sojo University 4-22-1 Ikeda Kumamoto 860-0082 Japan Johan Van de Voorde Ghent University Vascular Research Unit De Pintelaan 185 – Blok B 9000 Gent Belgium Han van de Waterbeemd AstraZeneca LG DECS, Global Compound Sciences Alderley Park, 50S39 Macclesfi eld Cheshire SK10 4TG UK Herbert Waldmann Max Planck Institute of Molecular Physiology Otto-Hahn-Str. 11 D-44227 Dortmund Germany CTR-P374194.indd xxxii TR-P374194.indd xxxii 5/30/2008 9:13:18 PM /30/2008 9:13:18 PM
Contributors ard Gonthier d'Andernach 67400 nIkirch Salt Lake City.UT84108 France USA Stefan Wetzel Max k Institute of Molecular Physiology Otto-Hahn-Str.11 D-44227 Dortmund Germany
Contributors xxxiii Camille G. Wermuth Prestwick Chemical Inc. Boulevard Gonthier d’Andernach 67400 Illkirch France Stefan Wetzel Max Planck Institute of Molecular Physiology Otto-Hahn-Str. 11 D-44227 Dortmund Germany Kenton H. Zavitz Myriad Genetics, Inc. 320 Wakara Way Salt Lake City, UT 84108 USA CTR-P374194.indd xxxiii TR-P374194.indd xxxiii 5/30/2008 9:13:18 PM /30/2008 9:13:18 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
☐xxxi Preface to the first edition eptanal r)Richard Baker (Wod.UK) cids. acids with hydrazine yields pyrodazones.Thus,all our John Topliss (University of Michigan.Ann Arbor)for their present research on pyridazine derivatives originates from invaluable assistance,comments and contributions pMythanks go also to the editoria nd Eron Kin n to the t editors Len Cegielka Preparing this book was a collective adventure and Iam and Peterr md fimallytoewsrearefou most grateful to all authors for their cooperation and for laboratory,Franqois Herth and Marylse Wernert the time and the effort they spent to write their respective Last but not least.I want to thank my wife Rene for al apprec expected. before my computer for about 2500 hours! I am very grateful to Brad Anderson (University of Utah,Salt Lake city).Jean-Jacques Andre(Marion Merrell Camille G.Wermuth
xxxvi Preface to the First Edition n-heptanal – and, more generally, of any enolisable aldehyde or ketone – with pyruvic acid leads to a-hydroxy- γ-ketonic acids. Finally, the condensation of these keto acids with hydrazine yields pyrodazones. Thus, all our present research on pyridazine derivatives originates from my schoolboy chemistry, when I prepared in my home in Mulhouse n-heptanal and undecylenic acid by cracking caster oil! Preparing this book was a collective adventure and I am most grateful to all authors for their cooperation and for the time and the effort they spent to write their respective contributions. I appreciate also their patience, especially as the editing process took much more time than initially expected. I am very grateful to Brad Anderson (University of Utah, Salt Lake city), Jean-Jacques André (Marion Merrell Dow, Strasbourg), Richard Baker (Eli Lilly, Erl Wood, UK), Thomas C. Jones (Sandoz, Basle), Isabelle Morin (Servier, Paris), Bryan Reuben (London South Bank University) and John Topliss (University of Michigan, Ann Arbor) for their invaluable assistance, comments and contributions. My thanks go also to the editorial staff of Academic Press in London, Particularly to Susan Lord, Nicola Linton and Fran Kingston, to the two copy editors Len Cegielka and Peter Cross, and fi nally, to the two secretaries of our laboratory, Franqois Herth and Marylse Wernert. Last but not least, I want to thank my wife Renée for all her encouragement and for sacrifi cing evenings an Saturday family life over the past year and a half, to allow me to sit before my computer for about 2500 hours! Camille G. Wermuth PRE-P374194.indd xxxvi RE-P374194.indd xxxvi 5/30/2008 9:13:33 PM /30/2008 9:13:33 PM