Table Of ContentBURGER'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
