Table Of ContentIntegration of
Pharmaceutical Discovery
and Development
Case Histories
Pharmaceutical Biotechnology
Series Editor: Ronald T. Borchardt
The University of Kansas
Lawrence, Kansas
Recent volumes in this series:
Volume 4 BIOLOGICAL BARRIERS TO PROTEIN DELIVERY
Edited by Kenneth L. Audus and Thomas J. Raub
Volume 5 STABILITY AND CHARACTERIZATION OF
PROTEIN AND PEPTIDE DRUGS: Case Histories
Edited by Y. John Wang and Rodney Pearlman
Volume 6 VACCINE DESIGN: The Subunit and Adjuvant Approach
Edited by Michael F. Powell and Mark J. Newman
Volume 7 PHYSICAL METHODS TO CHARACTERIZE
PHARMACEUTICAL PROTEINS
Edited by James N. Herron, Wim Jiskoot,
and Daan J. A. Crommelin
Volume 8 MODELS FOR ASSESSING DRUG ABSORPTION
AND METABOLISM
Edited by Ronald T. Borchardt,Philip L. Smith,
and Glynn Wilson
Volume 9 FORMULATION, CHARACTERIZATION, AND
STABILITY OF PROTEIN DRUGS: Case Histories
Edited by Rodney Pearlman and Y. John Wang
Volume 10 PROTEIN DELIVERY: Physical Systems
Edited by Lynda M. Sanders and R. Wayne Hendren
Volume 11 INTEGRATION OF PHARMACEUTICAL DISCOVERY
AND DEVELOPMENT: Case Histories
Edited by Ronald T. Borchardt, Roger M. Freidinger,
Tomi K. Sawyer, and Philip L. Smith
A Chronological Listing of Volumes in this series appears at the back of this volume
A Continuation Order Plan is available for this series. A continuation order will bring delivery of
each new volume immediately upon publication. Volumes are billed only upon actual shipment. For
further information pleasecontact the publisher.
Integration of
Pharmaceutical Discovery
and Development
Case Histories
Edited by
Ronald T. Borchardt
The University of Kansas
Lawrence, Kansas
Roger M. Freidinger
Merck Research Laboratories
West Point, Pennsylvania
Tomi K. Sawyer
ARIAD Pharmaceuticals, Inc.
Cambridge, Massachusetts
and
Philip L. Smith
SmithKline Beecham
Collegeville, Pennsylvania
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Contributors
Wade J. Adams • Discovery Chemistry, Pharmacia & Upjohn, Inc., Kalama-
zoo, Michigan 49001-0199
Akwete L. Adjei • Abbott Laboratories, North Chicago, Illinois 60064
Kimberly K. Adkison • Glaxo Wellcome Research and Development, Research
Triangle Park, North Carolina 27709
Fahad Al-Obeidi • Department of Chemistry, Selectide Research Center,
Hoechst-Marion Roussel, Tucson, Arizona 85724
Robert C. Andrews • Glaxo Wellcome Research and Development, Research
Triangle Park, North Carolina 27709
Paul A. Aristoff • Discovery Chemistry, Pharmacia & Upjohn, Inc., Kalama-
zoo, Michigan 49001-0199
Bruce J. Aungst • DuPont Merck Pharmaceutical Company, Experimental Sta-
tion, Wilmington, Delaware 19880-0500
Wilfried Bauer • Novartis Pharma AG, Basel, Switzerland CH-4002
Judd Berman • Glaxo Wellcome Research and Development, Research Trian-
gle Park, North Carolina 27709
Pradip K. Bhatnagar • Department of Medicinal Chemistry, SmithKline
Beecham Pharmaceuticals, King ofPrussia, Pennsylvania 19406-0939
v
vi Contributors
Lawrence Birkemo • Glaxo Wellcome Research and Development, Research
Triangle Park, North Carolina 27709
James Blanchard • Arizona Health Sciences Center, University of Arizona,
Tucson, Arizona 85724
Steven G. Blanchard • Glaxo Wellcome Research and Development, Research
Triangle Park, North Carolina 27709
David Bodmer • Novartis Pharma AG, Basel, Switzerland CH-4002
H. Neal Bramson • Glaxo Wellcome Research and Development, Research
Triangle Park, North Carolina 27709
Ulrich Briner • Novartis Pharma AG, Basel, Switzerland CH-4002
Peter J. Brown • Glaxo Wellcome Research and Development, ResearchTri-
angle Park, North Carolina 27709
Christian Bruns • Novartis Pharma AG, Basel, Switzerland CH-4002
George Burton • SmithKline Beecham Pharmaceuticals, Collegeville, Penn-
sylvania 19426-0989
Eugene N. Bush • Abbott Laboratories, North Chicago, Illinois 60064-3500
David J. Carini • DuPont Merck Pharmaceutical Company, Experimental Sta-
tion, Wilmington, Delaware 19880-0500
Kong Teck Chong • Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007
David D. Christ • DuPont Merck Pharmaceutical Company,Experimental Sta-
tion, Wilmington, Delaware 19880-0500
Brenda V. Dawson • Health Sciences, The University of Auckland, 92019
Auckland, New Zealand
George V. De Lucca • DuPont MerckPharmaceutical Company, Experimental
Station, Wilmington,Delaware 19880-0500
Annette M. Doherty • Department of Chemistry, Parke-Davis Pharmaceuti-
cal Research Division, Warner-Lambert Company, Ann Arbor, Michigan
48105
Contributors vii
Robert T. Dorr • Arizona Cancer Center, University of Arizona, Tucson, Ari-
zona 85724
David Drewry • Glaxo Wellcome Research and Development, Research Tri-
angle Park, NorthCarolina 27709
John V. Duncia • DuPont Merck PharmaceuticalCompany,Experimental Sta-
tion, Wilmington, Delaware 19880-0500
Geneviève Durand-Cavagna • Merck Sharp & Dohme-Chibret Research Cen-
ter, Riom, 63203 France
Harma M. Ellens • Department of Medicinal Chemistry, SmithKline Beecham
Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939
John D. Elliott • Department of Medicinal Chemistry, SmithKline Beecham
Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939
Susan Erickson-Viitanen • DuPont Merck Pharmaceutical Company, Experi-
mental Station, Wilmington, Delaware 19880-0500
Stephen V. Frye • Glaxo Wellcome Research and Development, Research Tri-
angle Park, North Carolina 27709
Kenneth W. Funk • Abbott Laboratories, North Chicago, Illinois 60064
Liang-Shang L. Gan • Glaxo Wellcome Research and Development, Research
Triangle Park, North Carolina 27709
Paul D. Gesellchen • Lilly Research Laboratories, Eli Lilly and Company, In-
dianapolis, Indiana 46285
Jonathan Greer • Abbott Laboratories, North Chicago, Illinois 60064-3500
Mac E. Hadley • Department of Cell Biology and Anatomy, University of Ari-
zona, Tucson, Arizona 85724
Kathy A. Halm • Glaxo Wellcome Research and Development, Research Tri-
angle Park, North Carolina 27709
Fortuna Haviv • Abbott Laboratories, North Chicago, Illinois 60064-3500
David J. Hermann • Glaxo Wellcome Research and Development, Research
Triangle Park, North Carolina 27709
viii Contributors
Joanna P. Hinton • Department of Pharmacokinetics and Drug Metabolism,
Parke-Davis Pharmaceutical Research, Warner-Lambert Company, Ann Ar-
bor, Michigan 48105
Ralph Hirschmann • Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323
Victor J. Hruby • Department of Chemistry, University of Arizona, Tucson,
Arizona 85724
William F. Huffman • Department of Medicinal Chemistry, SmithKline
Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939
Prabhakar K. Jadhav • DuPont Merck Pharmaceutical Company, Experimen-
tal Station, Wilmington, Delaware 19880-0500
Richard L. Jarvest • SmithKline Beecham Pharmaceuticals, Harlow, Essex
CM 19 5 AW, England
Richard K. Jensen • Discovery Chemistry, Pharmacia & Upjohn, Inc., Kala-
mazoo, Michigan 49001-0199
Andrea Kay • Novartis Pharma Ltd., East Hanover, New Jersey 07936
Andrew G. King • Department of Molecular Virology and Host Defense,
SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania 19426
Hollis D. Kleinert • Abbott Laboratories, North Chicago, Illinois 60064
Judith Knittle • Abbott Laboratories, North Chicago, Illinois 60064-3500
Kenneth A. Koeplinger • Pharmacia & Upjohn, Inc.,Kalamazoo, Michigan 49007
M. Amparo Lago • Department of Medicinal Chemistry, SmithKline Beecham
Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939
Patrick Y. S. Lam • DuPont Merck Pharmaceutical Company, Experimental
Station, Wilmington, Delaware 19880-0500
Ioana Lancranjan • Novartis Pharma AG, Basel, Switzerland CH-4002
Frank W. Lee • Glaxo Wellcome Research and Development, Research Trian-
gle Park, North Carolina 27709
Contributors ix
Norman Levine • Department of Dermatology, University of Arizona, Tucson,
Arizona 85724
Jiunn H. Lin • Drug Metabolism, Merck Research Laboratories, West Point,
Pennsylvania 19486
Franco Lombardo • Central Research Division, Pfizer Inc., Groton, Connecti-
cut 06340
Dagfinn Løvhaug • Nycomed Imaging AS, Bioreg Research, Oslo N0371,
Norway
John A. Lowe III • Central ResearchDivision, Pfizer Inc., Groton, Connecticut
06340
Peter Marbach • Novartis Pharma AG, Basel, Switzerland CH-4002
Linda Mizen • SmithKline Beecham Pharmaceuticals, Collegeville, Pennsyl-
vania 19426-0989
Walter Morozowich • Discovery Chemistry, Pharmacia & Upjohn, Inc., Kala-
mazoo, Michigan 49001-0199
Eliot H. Ohlstein • Department of Medicinal Chemistry, SmithKline Beecham
Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939
Drazen Ostovic • Pharmaceutical Research and Development, Merck Re-
searchLaboratories,West Point, Pennsylvania 19486
Guy E. Padbury • Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007
Arthur A. Patchett • Departments of Medicinal Chemistry and Biochemistry &
Physiology, MerckResearch Laboratories, Rahway, New Jersey 07065
Catherine E. Peishoff • Department of Medicinal Chemistry, SmithKline
Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939
Louis M. Pelus • Department of Molecular Virology and Host Defense,
SmithKline BeechamPharmaceuticals, Collegeville, Pennsylvania 19426
Michael E. Pierce • DuPont Merck Pharmaceutical Company, Experimental
Station, Wilmington, Delaware 19880-0500
x Contributors
Bernard Plazonnet • Merck Sharp & Dohme-Chibret Research Center, Riom,
63203 France
Janos Pless • Novartis Pharma AG, Basel, Switzerland CH-4002
Gerald S. Ponticello • Merck Research Laboratories, West Point, Pennsylva-
nia 19486
William M. Potts • Department of Drug Metabolism and Pharmacokinetics,
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-
0939
Thomas J. Raub • Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007
Friedrich Raulf • Novartis Pharma AG, Basel, Switzerland CH-4002
Rodney Robison • Novartis Pharma Ltd., East Hanover, New Jersey 07936
Donna L. Romero • Discovery Chemistry, Pharmacia & Upjohn, Inc., Kala-
mazoo, Michigan 49001-0199
Saul H. Rosenberg • Abbott Laboratories, North Chicago, Illinois 60064
Tomi K. Sawyer • Ariad Pharmaceuticals, Cambridge, Massachusetts 02139
William C. Schinzer • Discovery Chemistry, Pharmacia & Upjohn, Kalama-
zoo, Michigan 49001-0199
Francis J. Schwende • Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007
Joel E. Shaffer • Glaxo Wellcome Research and Development, Research Tri-
angle Park, North Carolina 27709
John Sharkey • Novartis Pharma Ltd., East Hanover, New Jersey 07936
Robert T. Shuman • Lilly Research Laboratories, Eli Lilly and Company, Indi-
anapolis, Indiana 46285
Achintya K. Sinhababu • Glaxo Wellcome Research and Development, Re-
searchTriangle Park, North Carolina 27709
Philip L. Smith • Department of Drug Delivery, SmithKline Beecham Phar-
maceuticals, Collegeville, Pennsylvania 19426
