BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY BURGER'S MEDICIN AL CHEMISTRY AND DRUG DISCOVERY Sixth Edition Volume 2: Drug Discovery and Drug Development Edited by Donald Abraham J. Department of Medicinal Chemistry School of Pharmacy Virginia Commonwealth University Richmond, Virginia Burger's Medicinal Chemistry and Drug Discovery is available Online in full color at www.mrw.interscience.wiley.com/bmcdd. A Wiley-Interscience Publication john Wiley and Sons, Inc. BURGER MEMORIAL EDITION The Sixth Edition of Burger's Medicinal laboratories, brought to market [Parnate, Chemistry and Drug Discovery is being desig- which is the brand name for tranylcypromine, nated as a Memorial Edition. Professor Alfred a monoamine oxidase (MAO) inhibitor]. Dr. Burger was born in Vienna, Austria on Sep- Burger was a visiting Professor at the Univer- tember 6, 1905 and died on December 30, sity of Hawaii and lectured throughout the 2000. Dr. Burger received his Ph.D. from the world. He founded the Journal of Medicinal University of Vienna in 1928 and joined the Chemistry, Medicinal Chemistry Research, Drug Addiction Laboratory in the Department and published the first major reference work of Chemistry at the University of Virginia in "Medicinal Chemistry" in two volumes in 1929. During his early years at WA, he syn- 1951. His last published work, a book, was thesized fragments of the morphine molecule written at age 90 (Understanding Medica- in an attempt to find the analgesic pharma- tions: What the Label Doesn't Tell You, June cophore. He joined the W Ac hemistry faculty 1995). Dr. Burger received the Louis Pasteur in 1938 and served the department until his Medal of the Pasteur Institute and the Amer- retirement in 1970. The chemistry depart- ican Chemical Society Smissman Award. Dr.' ment at W A became the major academic Burger played the violin and loved classical training ground for medicinal chemists be- music. He was married for 65 years to Frances cause of Professor Burger. Page Burger, a genteel Virginia lady who al- Dr. Burger's research focused on analge- ways had a smile and an open house for the sics, antidepressants, and chemotherapeutic Professor's graduate students and postdoc- agents. He is one of the few academicians to have a drug, designed and synthesized in his toral fellows. vii PREFACE The Editors, Editorial Board Members, and sixth edition, we devote an entire subsection John Wiley and Sons have worked for three of Volume 4 to cancer research; we have also and a half years to update the fifth edition of reviewed the major published Medicinal Burger's Medicinal Chemistry and Drug Dis- Chemistry and Pharmacology texts to ensure covery. The sixth edition has several new and that we did not omit any major therapeutic unique features. For the first time, there will classes of drugs. An editorial board was consti- be an online version of this major reference tuted for the first time to also review and sug- work. The online version will permit updating gest topics for inclusion. Their help was and easy access. For the first time, all volumes greatly appreciated. The newest innovation in are structured entirely according to content this series will be the publication of an aca- and published simultaneously. Our intention demic, "textbook-like" version titled, "Bur- was to provide a spectrum of fields that would ger's Fundamentals of Medicinal Chemistry." provide new or experienced medicinal chem- The academic text is to be published about a ists, biologists, pharmacologists and molecu- year after this reference work appears. It will lar biologists entry to their subjects of interest also appear with soft cover. Appropriate and as well as provide a current and global per- key information will be extracted from the ma- spective of drug design, and drug develop- jor reference. ment. There are numerous colleagues, friends, Our hope was to make this edition of and associates to thank for their assistance. Burger the most comprehensive and useful First and foremost is Assistant Editor Dr. published to date. To accomplish this goal, we John Andrako, Professor emeritus, Virginia expanded the content from 69 chapters (5 vol- Commonwealth University, School of Phar- umes) by approximately 50% (to over 100 macy. John and I met almost every Tuesday chapters in 6 volumes). We are greatly in debt for over three years to map out and execute to the authors and editorial board members the game plan for the sixth edition. His contri- participating in this revision of the major ref- bution to the sixth edition cannot be under- erence work in our field. Several new subject stated. Ms. Susanne Steitz, Editorial Program areas have emerged since the fifth edition ap- Coordinator at Wiley, tirelessly and meticu- peared. Proteomics, genomics, bioinformatics, lously kept us on schedule. Her contribution combinatorial chemistry, high-throughput was also key in helping encourage authors to screening, blood substitutes, allosteric effec- return manuscripts and revisions so we could tors as potential drugs, COX inhibitors, the publish the entire set at once. I would also like statins, and high-throughput pharmacology to especially thank colleagues who attended are only a few. In addition to the new areas, we the QSAR Gordon Conference in 1999 for very have filled in gaps in the fifth edition by in- helpful suggestions, especially Roy Vaz, John cluding topics that were not covered. In the Mason, Yvonne Martin, John Block, and Hugo x Preface Kubinyi. The editors are greatly indebted to Dukat, Martin Safo, Jason Rife, Kevin Reyn- Professor Peter Ruenitz for preparing a tem- olds, and John Andrako in our Department plate chapter as a guide for all authors. My of Medicinal Chemistry, School of Pharmacy, secretary, Michelle Craighead, deserves spe- Virginia Commonwealth University for sug- cial thanks for helping contact authors and gestions and special assistance in reviewing reading the several thousand e-mails gener- manuscripts and text. Graduate student ated during the project. I also thank the com- Derek Cashman took able charge of our web puter center at Virginia Commonwealth Uni- site, http:llwww.burgersmedchem.com, an- versity for suspending rules on storage and other first for this reference work. I would es- e-mail so that we might safely store all the pecially like to thank my dean, Victor versions of the author's manuscripts where Yanchick, and Virginia Commonwealth Uni- they could be backed up daily. Last and not versity for their support and encouragement. least, I want to thank each and every author, Finally, I thank my wife Nancy who under- some of whom tackled two chapters. Their stood the magnitude of this project and pro- contributions have provided our field with a vided insight on how to set up our home office sound foundation of information to build for as well as provide John Andrako and me the future. We thank the many reviewers of lunchtime menus where we often dreamed of manuscripts whose critiques have greatly en- getting chapters completed in all areas we se- hanced the presentation and content for the lected. To everyone involved, many, many sixth edition. Special thanks to Professors thanks. Richard Glennon, William Soine, Richard Westkaemper, Umesh Desai, Glen Kel- DONALD J. ABRAHAM logg, Brad Windle, Lemont Kier, Malgorzata Midlothian, Virginia CONTENTS 1 COMBINATORIAL CHEMISTRY 4 APPLICATION OF AND MULTIPLE PARALLEL RECOMBINANT DNA SYNTHESIS, 1 TECHNOLOGY IN MEDICINAL CHEMISTRY AND DRUG Lester A. Mitscher DISCOVERY, 81 Apurba Dutta Kansas University Soumitra Basu Department of Medicinal Chemistry University of Pittsburgh Lawrence, Kansas Center for Pharmacogenetics Department of Pharmaceutical Sciences 2 HIGH-THROUGHPUT Pittsburgh, Pennsylvania SCREENING FOR LEAD DISCOVERY, 37 Adegboyega K. Oyelere Rib-X Pharmaceuticals, Inc. John G. Houston New Haven, Connecticut Martyn N. Banks Pharmaceutical Research Institute Bristol-Myers Squibb 5 OLIGONUCLEOTIDE Wallingford, Connecticut THERAPEUTICS, 115 Stanley T. Crooke 3 HIGH-THROUGHPUT Isis Pharmaceuticals, Inc. PHARMACOLOGY, 71 Carlsbad, California Steven J. Brown Imran B. Clark 6 THERAPEUTIC AGENTS Bala Pandi ACTING ON RNA TARGETS, 167 Axiom Biotechnologies, Inc. Jason P. Rife San Diego, California Virginia Commonwealth University Richmond, Virginia xiii Contents xiv 7 CARBOHYDRATE-BASED 10 RECEPTOR TARGETS IN DRUG THERAPEUTICS, 203 DISCOVERY AND DEVELOPMENT, 319 John H. Musser Pharmagenesis, Inc. Michael Williams Palo Alto, California Department of Molecular Pharmacology and Biological 8 MEMBRANE TRANSPORT Chemistry PROTEINS AND DRUG Northwestern University Medical TRANSPORT, 249 School Peter W. Swam Chicago, Illinois Division of Pharmaceutics Christopher Mehlin Ohio State Biophysics Program Molecumetics Inc. OSU Heart & Lung Institute Core Bellevue, Washington Laboratory for Bioinformatics and David J. Triggle Computational Biology State University of New York The Ohio State University Buffalo, New York Columbus, Ohio 11 NICOTINIC ACETYLCHOLINE 9 ALLOSTERIC PROTEINS AND RECEPTORS, 357 DRUG DISCOVERY, 295 J. Ellis Bell David Colquhoun Department of Chemistry Chris Shelley Gottwald Science Center Chris Hatton University of Richmond Department of Pharmacology Richmond, Virginia University College London London, United Kingdom James C. Burnett School of Pharmacy and Nigel Unwin Department of Medicinal Chemistry Neurobiology Division Institute for Structural Biology and MRC Laboratory of Molecular Drug Discovery Biology Virginia Commonwealth University Cambridge, United Kingdom Richmond, Virginia Lucia Sivilotti Jessica K. Bell Department of Pharmacology Department of Pharmaceutical The School of Pharmacy Chemistry London, United Kingdom University of California at San Francisco 12 LARGE-SCALE SYNTHESIS, 407 San Francisco, California Frank Gupton Peter S. Galatin Boehringer Ingelheim Chemicals, Donald J. Abraham Inc. School of Pharmacy and Ridgefield, Connecticut Department of Medicinal Chemistry Institute for Structural Biology and Karl Grozinger Drug Discovery Boehringer Ingelheim Virginia Commonwealth University Pharmaceuticals, Inc. Richmond, Virginia Ridgefield, Connecticut 13 PRINCIPLES OF DRUG 17 DRUG ABSORPTION, METABOLISM, 431 DISTRIBUTION, AND ELIMINATION, 633 Bernard Testa School of Pharmacy Leslie Z. Benet University of Lausanne Beatrice Y. T. Perotti Institute of Medicinal Chemistry University of California Lausanne, Switzerland Department of Pharmacy San Francisco, California William Soine Virginia Commonwealth University Larry Hardy Department of Medicinal Chemistry Aurigene Discovery Technologies Richmond, Virginia Lexington, Massachusetts 14 METABOLIC CONSIDERATIONS 18 PHYSICOCHEMICAL IN PRODRUG DESIGN, 499 CHARACTERIZATION AND Luc P. Balant PRINCIPLES OF ORAL DOSAGE University Hospitals of Geneva FORM SELECTION, 649 Clinical Research Unit Gregory E. Amidon Department of Psychiatry Xiaorong He Geneva, Switzerland Michael J. Hageman Pharmacia Corporation 15 RETROMETABOLISM-BASED Kalamazoo, Michigan DRUG DESIGN AND TARGETING, 533 19 THE FDA AND REGULATORY Nicholas Bodor ISSUES, 683 Center for Drug Discovery W. Janusz Rzeszotarski University of Florida Food and Drug Administration Gainesville, Florida Rockville, Maryland and WAX Research, Inc. Miami, Florida 20 INTELLECTUAL PROPERTY IN DRUG DISCOVERY AND Peter Buchwald BIOTECHNOLOGY, 703 WAX Research, Inc. Miami, Florida Richard A. Kaba Timothy P. Maloney James P. Krueger 16 DRUG DISCOVERY: THE ROLE Rudy Kratz OF TOXICOLOGY, 609 Julius Tabin James B. Moe Fitch, Even, Tabin & Flannery James M. McKim, Jr. Chicago, Illinois Pharmacia Corporation Kalamazoo, Michigan INDEX, 783