Pharmaceutical Biotechnology
Series Editor: Ronald T. BorchardtThe University of KansasLawrence, Kansas
Recent volumes in this series:
Volume 4 BIOLOGICAL BARRIERS TO PROTEIN DELIVERYEdited by Kenneth L. Audus and Thomas J. Raub
Volume 5 STABILITY AND CHARACTERIZATION OFPROTEIN AND PEPTIDE DRUGS: Case HistoriesEdited by Y. John Wang and Rodney Pearlman
Volume 6 VACCINE DESIGN: The Subunit and Adjuvant ApproachEdited by Michael F. Powell and Mark J. Newman
Volume 7 PHYSICAL METHODS TO CHARACTERIZEPHARMACEUTICAL PROTEINSEdited by James N. Herron, Wim Jiskoot,and Daan J. A. Crommelin
Volume 8 MODELS FOR ASSESSING DRUG ABSORPTIONAND METABOLISMEdited by Ronald T. Borchardt, Philip L. Smith,and Glynn Wilson
Volume 9 FORMULATION, CHARACTERIZATION, ANDSTABILITY OF PROTEIN DRUGS: Case HistoriesEdited by Rodney Pearlman and Y. John Wang
Volume 10 PROTEIN DELIVERY: Physical SystemsEdited by Lynda M. Sanders and R. Wayne Hendren
Volume 11 INTEGRATION OF PHARMACEUTICAL DISCOVERYAND DEVELOPMENT: Case HistoriesEdited 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 wil l bring delivery ofeach new volume immediately upon publication. Volumes are billed only upon actual shipment. Forfurther information please contact the publisher.
Integration ofPharmaceutical Discoveryand DevelopmentCase Histories
Edited by
Ronald T. BorchardtThe University of Kansas
Lawrence, Kansas
Roger M. FreidingerMerck Research LaboratoriesWest Point, Pennsylvania
Tomi K. SawyerARIAD Pharmaceuticals, Inc.Cambridge, Massachusetts
and
Philip L. SmithSmithKline BeechamCollegeville, 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, ResearchTriangle 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, ResearchTriangle 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, SmithKlineBeecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939
v
vi Contributors
Lawrence Birkemo • Glaxo Wellcome Research and Development, ResearchTriangle Park, North Carolina 27709
James Blanchard • Arizona Health Sciences Center, University of Arizona,Tucson, Arizona 85724
Steven G. Blanchard • Glaxo Wellcome Research and Development, ResearchTriangle Park, North Carolina 27709
David Bodmer • Novartis Pharma AG, Basel, Switzerland CH-4002
H. Neal Bramson • Glaxo Wellcome Research and Development, ResearchTriangle Park, North Carolina 27709
Ulrich Briner • Novartis Pharma AG, Basel, Switzerland CH-4002
Peter J. Brown • Glaxo Wellcome Research and Development, Research Tri-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, 92019Auckland, New Zealand
George V. De Lucca • DuPont Merck Pharmaceutical Company, ExperimentalStation, Wilmington, Delaware 19880-0500
Annette M. Doherty • Department of Chemistry, Parke-Davis Pharmaceuti-cal Research Division, Warner-Lambert Company, Ann Arbor, Michigan48105
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, North Carolina 27709
John V. Duncia • DuPont Merck Pharmaceutical Company, 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 BeechamPharmaceuticals, King of Prussia, Pennsylvania 19406-0939
John D. Elliott • Department of Medicinal Chemistry, SmithKline BeechamPharmaceuticals, 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, ResearchTriangle 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, ResearchTriangle 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, SmithKlineBeecham 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, EssexCM 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 BeechamPharmaceuticals, King of Prussia, Pennsylvania 19406-0939
Patrick Y. S. Lam • DuPont Merck Pharmaceutical Company, ExperimentalStation, 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 Research Division, Pfizer Inc., Groton, Connecticut06340
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 BeechamPharmaceuticals, King of Prussia, Pennsylvania 19406-0939
Drazen Ostovic • Pharmaceutical Research and Development, Merck Re-search Laboratories, West Point, Pennsylvania 19486
Guy E. Padbury • Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007
Arthur A. Patchett • Departments of Medicinal Chemistry and Biochemistry &Physiology, Merck Research Laboratories, Rahway, New Jersey 07065
Catherine E. Peishoff • Department of Medicinal Chemistry, SmithKlineBeecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939
Louis M. Pelus • Department of Molecular Virology and Host Defense,SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania 19426
Michael E. Pierce • DuPont Merck Pharmaceutical Company, ExperimentalStation, 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-search Triangle Park, North Carolina 27709
Philip L. Smith • Department of Drug Delivery, SmithKline Beecham Phar-maceuticals, Collegeville, Pennsylvania 19426
Contributors xi
Roy G. Smith • Departments of Medicinal Chemistry and Biochemistry &Physiology, Merck Research Laboratories, Rahway, New Jersey 07065
Thomas Soranno • Novartis Pharma Ltd., East Hanover, New Jersey 07936
Barbara Stolz • Novartis Pharma AG, Basel, Switzerland CH-4002
Elizabeth E. Sugg • Glaxo Wellcome Research and Development, ResearchTriangle Park, North Carolina 27709
Michael F. Sugrue • Merck Research Laboratories, West Point, Pennsylvania19486
David Sutton • SmithKline Beecham Pharmaceuticals, Harlow, Essex CM 195AW, England
W. Gary Tarpley • Discovery Chemistry, Pharmacia & Upjohn, Inc., Kalama-zoo, Michigan 49001-0199
Suvit Thaisrivongs • Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007
Richard C. Thomas • Discovery Chemistry, Pharmacia & Upjohn, Inc., Kala-mazoo, Michigan 49001-0199
Gaochao Tian • Glaxo Wellcome Research and Development, Research Tri-angle Park, North Carolina 27709
Timothy K. Tippin • Glaxo Wellcome Research and Development, ResearchTriangle Park, North Carolina 27709
Larry Tremaine • Central Research Division, Pfizer Inc., Groton, Connecticut06340
Bharat K. Trivedi • Department of Medicinal Chemistry, Parke-Davis Phar-maceutical Research, Warner-Lambert Company, Ann Arbor, Michigan48105
Andrew C. G. Uprichard • Department of Cardiac and Vascular Diseases,Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company,Ann Arbor, Michigan 48105
Joseph P. Vacca • Medicinal Chemistry, Merck Research Laboratories, WestPoint, Pennsylvania 19486
xii Contributors
R. Anthony Vere Hodge • SmithKline Beecham Pharmaceuticals, Harlow, Es-sex CM 19 5 AW, England
Peter Vit • Novartis Pharma AG, Basel, Switzerland CH-4002
Robert E. Waltermire • DuPont Merck Pharmaceutical Company, Experimen-tal Station, Wilmington, Delaware 19880-0500
Gisbert Weckbecker • Novartis Pharma AG, Basel, Switzerland CH-4002
Thomas N. Wheeler • Glaxo Wellcome Research and Development, ResearchTriangle Park, North Carolina 27709
Steven M. Winter • Central Research Division, Pfizer Inc., Groton, Connecti-cut 06340
Matthew J. Wyvratt • Departments of Medicinal Chemistry and Biochemistry& Physiology, Merck Research Laboratories, Rahway, New Jersey 07065
Zhiyang Zhao • Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007
Gail L. Zipp • Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007
Preface
In the late 1980s, it became painfully evident to the pharmaceutical industry thatthe old paradigm of drug discovery, which involved highly segmented drug de-sign and development activities, would not produce an acceptable success rate inthe future. Therefore, in the early 1990s a paradigm shift occurred in which drugdesign and development activities became more highly integrated. This new strat-egy required medicinal chemists to design drug candidates with structural fea-tures that optimized pharmacological (e.g., high affinity and specificity for thetarget receptor), pharmaceutical (e.g., solubility and chemical stability), biophar-maceutical (e.g., cell membrane permeability), and metabolic/pharmacokinetic(e.g., metabolic stability, clearance, and protein binding) properties. Successfulimplementation of this strategy requires a multidisciplinary team effort, includ-ing scientists from drug design (e.g., medicinal chemists, cell biologists, enzy-mologists, pharmacologists) and drug development (e.g., analytical chemists,pharmaceutical scientists, physiologists, and molecular biologists representingthe disciplines of pharmaceutics, biopharmaceutics, and pharmacokinetics/drugmetabolism).
With this new, highly integrated approach to drug design now widely utilizedby the pharmaceutical industry, the editors of this book have provided the scien-tific community with case histories to illustrate the nature of the interdisciplinaryinteractions necessary to successfully implement this new approach to drug dis-covery. In the first chapter, Ralph Hirschmann provides a historical perspective ofwhy this paradigm shift in drug discovery has occurred. Subsequent chapters de-scribe in detail the strategies used to discover the following drugs or drug candi-dates: renin inhibitors (Chapter 2, S. H. Rosenberg and H. D. Kleinert, Abbott Lab-oratories); angiotensin II antagonists (Chapter 3, D. Carini et al., DuPont Merck);thrombin inhibitors (Chapter 4, R. T. Shuman and P. D. Gesellchen, Lilly ResearchLaboratories); endothelin receptor antagonists (Chapter 5, A. M. Doherty andA. C. G. Uprichard, Parke-Davis; Chapter 6, J. D. Elliott et al., SmithKline
xiii
xiv Preface
Beecham); LHRH antagonists (Chapter 7, F. Haviv et al., Abbott Laboratories);LHRH agonists (Chapter 8, K. W. Funk et al., Abbott Laboratories); somatostatinagonists (Chapter 9, P. Marbach et al., Novartis); HIV protease inhibitors (Chap-ter 10, G. E. Padbury et al., Pharmacia & Upjohn; Chapter 11, J. H. Lin et al.,Merck Research Laboratories; Chapter 12, G. V. De Lucca et al., DuPont Merck);reverse transcriptase inhibitors (Chapter 13, W. J. Adams et al., Pharmacia & Up-john); antiherpesvirus agents (Chapter 14, R. L. Jarvest et al., SmithKlineBeecham); ester prodrugs of antibiotics (Chapter 15, L. Mizen and G.Burton, SmithKline Beecham); hematoregulators (Chapter 16, P. K. Bhatnagar etal., SmithKline Beecham), inhibitors of (Chapter 17, S. V. Frye etal., Glaxo Wellcome); receptor antagonists (Chapter 18, K. K. Adkison et al.,Glaxo Wellcome); inhibitors of secretory phospholipase (Chapter 19, S. G.Blanchard et al., Glaxo Wellcome); CCK-B receptor antagonists (Chapter 20, F.Lombardo et al., Pfizer; Chapter 21, B. K. Trivedi and J. P. Hinton, Parke-Davis);CCK-A agonists (Chapter 22, E. E. Sugg et al., Glaxo Wellcome); growth hormonesecretagogues (Chaper 23, A. A. Patchett et al., Merck Research Laboratories);carbonic anhydrase inhibitors (Chapter 24, G. S. Ponticello et al., Merck ResearchLaboratories); and melanotropic peptides (Chapter 25, M. E. Hadley et al., Uni-versity of Arizona, University of Auckland, Hoechst-Marion Roussel, and AriadPharmaceuticals).
Lastly, we thank all of the authors for their valuable and timely contributions.We hope that the case histories presented in this book will illustrate the benefits ofthis highly integrated approach to drug discovery and will facilitate the discoveryof novel drugs in the future.
Contents
Chapter 1
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Ralph Hirschmann
Chapter 2
Renin InhibitorsSaul H. Rosenberg and Hollis D. Kleinert
1.2.3.
4.
3.1.3.2.3.3.3.4.
The Renin Angiotensin System (RAS) . . . . . . . . . . . . . . . . . . . . . . . . . .In Vitro Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Renin Inhibitor Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Novel Transition-State Analogues . . . . . . . . . . . . . . . . . . . . . . . . . .Models to Evaluate Pharmacological Responses . . . . . . . . . . . . . . .Molecular Weight, Proteolytic Stability, and Aqueous Solubility . .Renin Inhibitors with Oral Bioavailability . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 3
The Discovery and Development of Angiotensin II AntagonistsDavid J. Carini, David D. Christ, John V. Duncia, and Michael E. Pierce
1.2.
2.1.2.2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Development of a Tetrazole Derivative . . . . . . . . . . . . . . . . . . . . . . . . . .
Chemical Stability and Potential Toxicity of Tetrazoles . . . . . . . . .Metabolism of Tetrazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
78
10101213172425
29303032
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xvi Contents
2.3.2.4.
The Search for Tetrazole Replacements . . . . . . . . . . . . . . . . . . . . . .Synthetic Availability of Biphenyltetrazoles . . . . . . . . . . . . . . . . . . .
An Active Metabolite of Losartan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.1.3.2.3.3.
Identification of EXP3174 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Should We Develop EXP3174? . . . . . . . . . . . . . . . . . . . . . . . . . . . .The Search for a Superior EXP3174 Analogue . . . . . . . . . . . . . . . .
3.
4.5.6.
Early Evaluation of Losartan’s Activity in Humans . . . . . . . . . . . . . . . .Selective versus Balanced Angiotensin II Receptor Antagonists . . . . . . .Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 4
Development of an Orally Active Tripeptide Arginal Thrombin InhibitorRobert T. Shuman and Paul D. Gesellchen
1.2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Identification of Lead Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.1.2.2.
In Vitro Structure–Activity Relationships . . . . . . . . . . . . . . . . . . . .In Vivo Structure–Activity Relationships . . . . . . . . . . . . . . . . . . . . .
Development of Parenteral Clinical Candidate . . . . . . . . . . . . . . . . . . . .3.1.3.2.
Development of Licensed Compound (Efegatran) . . . . . . . . . . . . .Summary of Clinical Data on Efegatran . . . . . . . . . . . . . . . . . . . . .
Development of an Oral Candidate . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4.1.4.2.4.3.4.4.
In Vivo Oral Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Oral Dosing in Efficacy Models . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmacokinetics of Oral Candidate . . . . . . . . . . . . . . . . . . . . . . . .Clinical Data for Oral Candidate . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 5
Discovery and Development of an Endothelin A Receptor-SelectiveAntagonist PD 156707Annette M. Doherty and Andrew C. G. Uprichard
1.2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Discovery of PD 156707: Medicinal Chemistry, Pharmacology,and Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33394444454547485152
5760616469697070717373757778
81
84
Contents xvii
2.1.2.2.2.3.2.4.2.5.2.6.2.7.
Identification of Lead Structures . . . . . . . . . . . . . . . . . . . . . . . . . . .Structure–Activity Relationships . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmacokinetics/Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Chemistry/Chemical Development . . . . . . . . . . . . . . . . . . . . . . . .Biological Evaluation of PD 156707 . . . . . . . . . . . . . . . . . . . . . . .Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Assay Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Efficacy Studies: Which Disease States? . . . . . . . . . . . . . . . . . . . . . . . . .3.1.3.2.3.3.3.4.
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Future Plans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 6
Endothelin Receptor AntagonistsJohn D. Elliott, Eliot H. Ohlstein, Catherine E. Peishoff, Harma M. Ellens,and M. Amparo Lago
1.2.3.
4.5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Rational Design of SB 209670 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmacological, Drug Metabolism, and PharmacokineticCharacterization of SB 209670 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Selection of the Orally Bioavailable Candidate SB 217242 . . . . . . . . . .Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 7
LHRH AntagonistsFortuna Haviv, Eugene N. Bush, Judith Knittle, and Jonathan Greer
1.2.
Mechanism of Action of LHRH Agonists and Antagonists . . . . . . . . . .Structural Differences of LHRH Agonists and Antagonists . . . . . . . . . .2.1. Reduction of Size of LHRH Analogues . . . . . . . . . . . . . . . . . . . . . .
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100103103105105
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xviii Contents
2.2.
2.3.
Enzymatic Stability of LHRH Analogues and Effect of N-methylSubstitution on Enzymatic Stability of LHRH Agonists . . . . . . . . .Effect of N-methyl Substitution on Water Solubility of LHRHAntagonists. Discovery of A-75998 . . . . . . . . . . . . . . . . . . . . . . . . .
3. Biological Testing Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.1.
3.2.3.3.
In Vitro Testing of A-75998: Receptor Binding, Inhibition of LHRelease, and Histamine Release . . . . . . . . . . . . . . . . . . . . . . . . . . . .In Vivo Studies of A-75998 in Rat, Dog, and Monkey . . . . . . . . . . .Pharmacokinetics of A-75998 in Rat, Dog, and Monkey . . . . . . . .
4.5.
6.
Aggregation and Formulation of A-75998 . . . . . . . . . . . . . . . . . . . . . . . .LHRH Antagonists in Clinical Evaluation . . . . . . . . . . . . . . . . . . . . . . . .5.1.5.2.
Clinical Study of A-75998 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Current LHRH Antagonists in Clinical Studies . . . . . . . . . . . . . . . .
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 8
LHRH AgonistsKenneth W. Funk, Jonathan Greer, and Akwete L. Adjei
1.
2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1.1.1.2.
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Drug Candidate Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Physical Chemistry and Chemical Characterization . . . . . . . . . . . . . . . .2.1.2.2.2.3.2.4.2.5.2.6.
Bulk Drug Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Manufacturing Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Physical Characteristics and Methods . . . . . . . . . . . . . . . . . . . . . . .Chemical Characterization and Methods . . . . . . . . . . . . . . . . . . . . .Moisture and Acetic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Amino Acid Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Formulation Chemistry of Leuprolide Acetate . . . . . . . . . . . . . . . . . . . .3.1.3.2.
In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .In Vivo Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4.1.4.2.4.3.4.4.
Standards and Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Physical and Chemical Characterization . . . . . . . . . . . . . . . . . . . . .Pathology and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Clinical Pharmacokinetics and Pharmacodynamics . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
136
137137
138138140141144144144146146
151152153157158160161163163164165165166169169171174177178179
Contents xix
Chapter 9
Discovery and Development of Somatostatin AgonistsPeter Marbach, Wilfried Bauer, David Bodmer, Ulrich Briner, Christian Bruns,Andrea Kay, Ioana Lancranjan, Janos Pless, Friedrich Raulf, Rodney Robison,John Sharkey, Thomas Soranno, Barbara Stolz, Peter Vit, and GisbertWeckbecker
1.2.
3.
4.
5.
6.
7.
8.
9.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Somatostatin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.1.2.2.2.3.2.4.
Heterogeneity of Somatostatin Receptors . . . . . . . . . . . . . . . . . . . .The Somatostatin Receptor Gene Family . . . . . . . . . . . . . . . . . . . .Tissue Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discovery and Development of Sandostatin® . . . . . . . . . . . . . . . . . . . . .3.1.3.2.3.3.3.4.3.5.
Synthesis of Octreotide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmacodynamic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmacokinetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Clinical Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Development of Sandostatin® LAR® . . . . . . . . . . . . . . . . . . . . . . . . . . .4.1.4.2.4.3.
Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Preclinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Oncolar™: Technical Development of a New LAR Formulationof Octreotide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.1.5.2.
Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Preclinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Antiproliferative Effects of Single-Agent Octreotide . . . . . . . . . . . . . . .6.1.6.2.6.3.
Mechanism of Antiproliferative Action . . . . . . . . . . . . . . . . . . . . . .Route of Administration and Plasma Levels . . . . . . . . . . . . . . . . . .Octreotide as a Potentiator of Standard Anticancer Regimens . . . .
Development of Octreotide for Oncological Uses beyond the Controlof Disease-Related Symptoms in GEP Tumors . . . . . . . . . . . . . . . . . . . .7.1.
7.2.
Somatostatin Receptor Binding and Growth FactorSuppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Radiolabeled Octreotide Analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8.1.8.2.
Imaging of Tumors with OctreoScan® . . . . . . . . . . . . . . . . . . . . . . .Tumor Radiotherapy with SMT 487 . . . . . . . . . . . . . . . . . . . . . . . .
Summary and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
183184184184185186186189190191191192193194194195
196196196197198199199
201
201202202203203204205
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Chapter 10
Factors Impacting the Delivery of Therapeutic Levels of Pyrone-Based HIVProtease InhibitorsGuy E. Padbury, Gail L. Zipp, Francis J. Schwende, Zhiyang Zhao, Kenneth A.Koeplinger, Kong Teck Chong, Thomas J. Raub, and Suvit Thaisrivongs
1.
2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1.1.1.2.1.3.1.4.
HIV Protease as a Therapeutic Target . . . . . . . . . . . . . . . . . . . . . . .Pyrone-Based Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Factors that Affect Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . .Life in a Perfect World . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.1.2.2.
Effect/Importance or Protein Binding . . . . . . . . . . . . . . . . . . . . . . .Clinical Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.1.3.2.3.3.
Total versus Unbound Intrinsic Clearance . . . . . . . . . . . . . . . . . . . .Factors Affecting Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Absolute Oral Bioavailability versus Systemic Exposure . . . . . . . .
Life in the Real World . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4.1.4.2.
Selection of a Viable Chemical Template . . . . . . . . . . . . . . . . . . . .Identification of a Final Clinical Candidate . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 11
The Integration of Medicinal Chemistry, Drug Metabolism, andPharmaceutical Research and Development in Drug Discovery andDevelopment: The Story of Crixivan®, an HIV Protease InhibitorJiunn H. Lin, Drazen Ostovic, and Joseph P. Vacca
1.2.3.4.5.6.7.8.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Discovery of L-735,524 (Crixivan®) . . . . . . . . . . . . . . . . . . . . . . . . . . . .Improvement of Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Physicochemical Properties of MK-639 (Indinavir) . . . . . . . . . . . . . . . .pH-Dependent Oral Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .In Vitro/In Vivo Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Backup Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
211211213215215216216219220220221224225225227229
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Chapter 12
De Novo Design and Discovery of Cyclic HIV Protease Inhibitors Capableof Displacing the Active-Site Structural Water MoleculeGeorge V. De Lucca, Prabhakar K. Jadhav, Robert E. Waltermire, Bruce J.Aungst, Susan Erickson-Viitanen, and Patrick Y. S. Lam
1.2.3.
4.
5.
6.
7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Initiation of Program at DMPC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Design of Cyclic Ureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.1.3.2.3.3.
De Novo Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Confirmation of Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Molecular Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
First Clinical Candidate DMP 323 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4.1.4.2.4.3.
Discovery and Optimization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Chemistry and Process Development . . . . . . . . . . . . . . . . . . . . . . .Clinical Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Second Clinical Candidate DMP 450 . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.1.5.2.5.3.5.4.
Discovery and Optimization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Safety and Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Chemistry and Process Development . . . . . . . . . . . . . . . . . . . . . . .Clinical Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Future Cyclic Ureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6.1.6.2.6.3.6.4.
Potency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Resistance Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Design and Physicochemical Properties . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 13
Discovery and Development of the BHAP Nonnucleoside ReverseTranscriptase Inhibitor Delavirdine MesylateWade J. Adams, Paul A. Aristoff, Richard K. Jensen, Walter Morozowich,Donna L. Romero, William C. Schinzer, W. Gary Tarpley,and Richard C. Thomas
1.2.
Introduction, Goals, and Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Discovery of Initial Lead (PNU-80493E) . . . . . . . . . . . . . . . . . . . . . . . .
257258259259262265266266267270270270271272273274275276278280280281
285287
xxii Contents
3.4.5.6.7.8.
9.
Selection of First-Generation Candidate (PNU-87201) . . . . . . . . . . . . . .Development of PNU-87201E (Atevirdine M e s y l a t e ) . . . . . . . . . . . . . . .Goals for Second-Generation Candidate . . . . . . . . . . . . . . . . . . . . . . . . .Selection Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Water-Soluble Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Development of PNU-90152T (Delavirdine Mesylate) . . . . . . . . . . . . . .8.1.8.2.8.3.8.4.8.5.
Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Formulation/Salt Selection/Crystal Form . . . . . . . . . . . . . . . . . . . .Absorption, Distribution, Metabolism, and Excretion . . . . . . . . . . .Safety/Toxicokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Clinical Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 14
Famciclovir: Discovery and Development of a Novel Antiherpesvirus AgentRichard L. Jarvest, David Sutton, and R. Anthony Vere Hodge
1.
2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1.1.1.2.1.3.1.4.
Identification of Penciclovir as an Antiherpesvirus Agent . . . . . . . .Antiviral Activity and Spectrum of Activity . . . . . . . . . . . . . . . . . .Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Oral Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Prodrug Forms of Penciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.1.2.2.
2.3.2.4.
Strategy and Evaluation of Oral Bioavailability . . . . . . . . . . . . . . .Evaluation of Metabolic Conversion in Human Body Fluidsand Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Selection of Preferred Oral Candidate: Famciclovir . . . . . . . . . . . .Other Routes of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Preclinical Evaluation of Famciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . .3.1.3.2.3.3.
Animal Models of Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Chirality of Metabolic Products from Famciclovir . . . . . . . . . . . . .Identification of Enzymatic Oxidation in Humans . . . . . . . . . . . . . .
Clinical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4.1.4.2.
Metabolism and Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . .Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 15
The Use of Esters as Prodrugs for Oral Delivery of AntibioticsLinda Mizen and George Burton
1.2.3.
4.
5.6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Chemical Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Animal Bioavailability Studies and Selection . . . . . . . . . . . . . . . . . . . . .3.1.3.2.
Penicillins, Penems, Trinem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Cephalosporins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hydrolysis Rates and Physicochemical Properties . . . . . . . . . . . . . . . . .4.1.4.2.4.3.4.4.
Hydrolysis by Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Hydrolysis by Small Intestine . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Hydrolysis by Blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Physicochemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Dosing Vehicles and Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 16
Hematoregulators: A Case History of a Novel Hematoregulatory Peptide,SK&F 107647Pradip K. Bhatnagar, William F. Huffman, Andrew G. King, Dagfinn Løvhaug,Louis M. Pelus, William M. Potts, Philip L. Smith
1.2.
3.4.
5.
6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Hematopoiesis, Endogenous Regulators, and Host DefenseMechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Unmet Needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Nonproteinaceous Hematoregulators . . . . . . . . . . . . . . . . . . . . . . . . . . . .4.1.4.2.
Polymeric Carbohydrate: Betafectin . . . . . . . . . . . . . . . . . . . . . . . .Low-Molecular-Weight Hematoregulators . . . . . . . . . . . . . . . . . . .
SK&F 107647 and Analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.1.5.2.5.3.5.4.5.5.
Structure–Activity Relationships of SK&F 107647 . . . . . . . . . . . .Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Colony Stimulating Activity Induction Assay . . . . . . . . . . . . . . . . .Hematopoietic Synergistic Factor Assay . . . . . . . . . . . . . . . . . . . . .Preclinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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367
368369371371371375376379379379380383384
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Chapter 17
Discovery and Development of GG745, a Potent Inhibitor of Both Isozymesof ReductaseStephen V. Frye, H. Neal Bramson, David J. Hermann, Frank W. Lee,Achintya K. Sinhababu, and Gaochao Tian
1.
2.
3.
4.5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1.1.1.2.1.3.
1.4.Enzymology of Reductases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reductases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pathophysiology of DHT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Finasteride: Clinical Effects of a Type 2-Selective ReductaseInhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Potential Utility of a Dual Reductase Inhibitor . . . . . . . . . . . . .
2.1.2.2.
Time Dependence of Inhibition by 4-Azasteroids . . . . . . . . . . .Modeling of the Clinical Effect of Finasteride . . . . . . . . . . . . . . . .
Discovery of Dual Reductase Inhibitors: 6-Azasteroids . . . . . . . . . .3.1.3.2.
Medicinal Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmacokinetic Studies: In Vivo and in Vitro Correlations . . . . . .
Discovery of GG745 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Initial Clinical Studies with GG745 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.1.5.2.
Interspecies Scaling/Dose Selection . . . . . . . . . . . . . . . . . . . . . . . .Pharmacokinetic and Pharmacodynamic Results in Man . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 18
Discovery of a Potent and Selective Antagonist: Utilization of a RapidScreening Method to Obtain Pharmacokinetic ParametersKimberly K. Adkison, Kathy A. Halm, Joel E. Shaffer, David Drewry,Achintya K. Sinhababu, and Judd Berman
1.
2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1.1.1.2.1.3.
Benign Prostatic Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Therapeutic Use of Selective Antagonists . . . . . . . . . . . . . . . .Project Goal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Research Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.1.2.2.
Compound Progression and Critical Path . . . . . . . . . . . . . . . . . . . .Discovery of Selective Oxazole-Containing Antagonists . . . .
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3.
4.
Pharmacokinetic/Pharmacodynamic Strategy . . . . . . . . . . . . . . . . . . . . .3.1.
3.2.
3.3.3.4.
In Vitro Metabolism Screening Prior to PharmacokineticStudies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Improved Pharmacokinetic Throughput: Mixture DosingCoupled with LC/MS Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmacokinetic Evaluation of Other Leads . . . . . . . . . . . . . . . . . .Pharmacodynamics of the Lead Compound . . . . . . . . . . . . . . . . . .
Advancement of Compound 18 to Exploratory D e v e l o p m e n t . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 19
Discovery of Bioavailable Inhibitors of Secretory Phospholipase A2
Steven G. Blanchard, Robert C. Andrews, Peter J. Brown, Liang-Shang L. Gan,Frank W. Lee, Achintya K. Sinhababu, and Thomas N. Wheeler
1.
2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1.1.1.2.
Therapeutic Target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Program Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
In Vitro Identification of Active-Site Inhibitors of sPLA2 . . . . . . . . . . . .2.1.2.2.
“Dual Substrate” Strategy for Inhibitor Discovery . . . . . . . . . . . . .In Vitro Profile of Substrate Analogue PLA2 Inhibitors . . . . . . . . . .
In Vivo Anti-inflammatory Activity of Initial Candidates . . . . . . . . . . . .3.1.3.2.
3.3.
Choice of Animal Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .In Vivo Activity Is Dependent on Formulation of the TestCompound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Activity in the Rat Carrageenan Paw Edema Model . . . . . . . . . . . .
Pharmacokinetic and Metabolic Fate of Candidate Inhibitors . . . . . . . . .4.1.4.2.4.3.
Plasma Levels and Metabolic Profiles after i.v. and p.o. Dosing . . .In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Conclusions Based on Metabolism Studies . . . . . . . . . . . . . . . . . . .
Preparation of Inhibitors Designed to Address the Observed MetabolicInstability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.1.5.2.5.3.5.4.
Synthesis and in Vitro Evaluation of Inhibitory Activity . . . . . . . . .Evaluation of in Vitro Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmacokinetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .In Vivo Activity of Inhibitors with Improved Metabolismand Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
433
433
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6. Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 20
The Anxieties of Drug Discovery and Development:CCK-B Receptor AntagonistsFranco Lombardo, Steven M. Winter, Larry Tremaine, and John A. Lowe III
1.2.3.4.5.6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Initial Drug Metabolism Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Formulation Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .A New Analogue with Improved Aqueous Solubility: CP-310,713 . . . .Lessons Learned . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 21
CI-1015: An Orally Active CCK-B Receptor Antagonist with an ImprovedPharmacokinetic ProfileBharat K. Trivedi and Joanna P. Hinton
1.
2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1.1.1.2.1.3.
First-Generation CCK-B Antagonists . . . . . . . . . . . . . . . . . . . . . . .CI-988 Pharmacokinetic Retrospective . . . . . . . . . . . . . . . . . . . . . .Objectives of the Discovery Team . . . . . . . . . . . . . . . . . . . . . . . . . .
Discovery of CI-1015 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.1.2.2.
Design Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Structure–Activity Relationship Study . . . . . . . . . . . . . . . . . . . . . .
Preclinical Characterization of Backup Candidates . . . . . . . . . . . . . . . . .3.1.3.2.3.3.3.4.3.5.
In Vitro and in Vivo Comparison . . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmacokinetic Evaluations in Rat . . . . . . . . . . . . . . . . . . . . . . . .Brain Penetration Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Evaluation of Potential for Gastric Acid Secretion . . . . . . . . . . . . .Pharmacokinetic Evaluation in Monkey . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 22
Orally Active Nonpeptide CCK-A AgonistsElizabeth E. Sugg, Lawrence Birkemo, Liang-Shang L. Gan,and Timothy K. Tippin
1.2.3.
4.
5.6.
7.8.9.
10.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .In Vivo Profile of GW7854 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmaceutical Studies with GW7854 . . . . . . . . . . . . . . . . . . . . . . . . .3.1.3.2.
Batch Variation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Dosing Vehicle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pharmacology Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4.1.4.2.4.3.
The Mouse Gallbladder Emptying Assay . . . . . . . . . . . . . . . . . . .Alternate Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .The Conditioned Feeder Rat Model . . . . . . . . . . . . . . . . . . . . . . . .
Pharmacokinetic Profile of GW7854 . . . . . . . . . . . . . . . . . . . . . . . . . . .The Caco-2 Model for Intestinal Absorption . . . . . . . . . . . . . . . . . . . . .6.1.6.2.
Correlation with Rat Intestinal Absorption . . . . . . . . . . . . . . . . . .Structure–Transport Relationships . . . . . . . . . . . . . . . . . . . . . . . . .
Bioavailability versus Bioactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Oral versus Intraduodenal Dosing . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 23
Orally Active Growth Hormone SecretagoguesArthur A. Patchett, Roy G. Smith, and Matthew J. Wyvratt
1.2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Discovery of GHRP-6 Mimics: Benzolactam L-692,429 . . . . . . . . . . . .2.1.2.2.
Clinical Studies with L-692,429 . . . . . . . . . . . . . . . . . . . . . . . . . . .Structure–Activity–Bioavailability Relationshipsfor the Benzolactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
New Structural Leads . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.1.3.2.
Privileged Structure Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Discovery of MK-0677 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Mechanism of Action of GH Secretagogues . . . . . . . . . . . . . . . . . . . . . .4.1. Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.2.4.3.4.4.
Characterization of the GH Secretagogue Receptor (GHS-R) . . . . .Cloning the GH Secretagogue Receptor . . . . . . . . . . . . . . . . . . . . .GH Secretagogue Receptor and GH Pulsatility . . . . . . . . . . . . . . . .
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 24
Dorzolamide, a 40-Year Wait: From an Oral to a Topical CarbonicAnhydrase Inhibitor for the Treatment of GlaucomaGerald S. Ponticello, Michael F. Sugrue, Bernard Plazonnet, and GenevièveDurand-Cavagna
1.2.3.4.5.6.
7.8.9.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Benzothiazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Benzothiophenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Thienothiopyrans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Dorzolamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6.1.6.2.
In Vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .In Vivo ...............................................
Pharmaceutical Research and Development Studies . . . . . . . . . . . . . . . .Safety Assessment Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 25
Discovery and Development of Novel Melanogenic Drugs:Melanotan-I and -IIMac E. Hadley, Victor J. Hruby, James Blanchard, Robert T. Dorr, NormanLevine, Brenda V. Dawson, Fahad Al-Obeidi, and Tomi K. Sawyer
1.2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .The Melanocortin Peptides and Receptors . . . . . . . . . . . . . . . . . . . . . . . .2.1.2.2.
Melanocortin Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Melanocortin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discovery of the MT-I and MT-II as MSH Superagonists . . . . . . . . . . . .3.1.3.2.
Structure–Activity Studies of . . . . . . . . . . . . . . . . . . . . . . .Design and Chemistry of MT-I and MT-II . . . . . . . . . . . . . . . . . . . .
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3.3.4.
5.
In Vitro and in Vivo Pharmacology of MT-I and MT-II . . . . . . . . . .Development of MT-I and MT-II as Novel Melanogenic Drugs . . . . . . .4.1.4.2.
Stability, Pharmacokinetic, and Toxicological Studies . . . . . . . . . .Drug Delivery and Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . .
Summary and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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