integration of pharmaceutical discovery and development978-0-306-47384-5/1 · edited by y. john...

Integration ofPharmaceutical Discoveryand DevelopmentCase Histories

Pharmaceutical Biotechnology

Series Editor: Ronald T. BorchardtThe University of KansasLawrence, Kansas

Recent volumes in this series:

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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

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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

xv

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 . . . . . . . . . . . . . . . . . . . . . .

84868789909293969699

100103103105105

113115

121121127127

131133135

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

xx Contents

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 . . . . . . . . . . . . . . . . . . . . .


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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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313314315316321321321

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Contents xxiii

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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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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 . . . . . . . . . . . . . . . . . . . . .


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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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