Integration of Pharmaceutical Discovery and Development

1. Front Matter

   Pages i-xxix

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2. Introduction

   • Ralph Hirschmann

   Pages 1-5

3. Renin Inhibitors

   • Saul H. Rosenberg, Hollis D. Kleinert

   Pages 7-28

4. The Discovery and Development of Angiotensin II Antagonists

   • David J. Carini, David D. Christ, John V. Duncia, Michael E. Pierce

   Pages 29-56

5. Development of an Orally Active Tripeptide Arginal Thrombin Inhibitor

   • Robert T. Shuman, Paul D. Gesellchen

   Pages 57-80

6. Discovery and Development of an Endothelin a Receptor-Selective Antagonist PD 156707

   • Annette M. Doherty, Andrew C. G. Uprichard

   Pages 81-112

7. Endothelin Receptor Antagonists

   • John D. Elliott, Eliot H. Ohlstein, Catherine E. Peishoff, Harma M. Ellens, M. Amparo Lago

   Pages 113-129

8. LHRH Antagonists

   • Fortuna Haviv, Eugene N. Bush, Judith Knittle, Jonathan Greer

   Pages 131-149

9. LHRH Agonists

   • Kenneth W. Funk, Jonathan Greer, Akwete L. Adjei

   Pages 151-182

10. Discovery and Development of Somatostatin Agonists

    • Peter Marbach, Wilfried Bauer, David Bodmer, Ulrich Briner, Christian Bruns, Ioana Lancranjan et al.

    Pages 183-209

11. Factors Impacting the Delivery of Therapeutic Levels of Pyrone-Based HIV Protease Inhibitors

    • Guy E. Padbury, Gail L. Zipp, Francis J. Schwende, Zhiyang Zhao, Kenneth A. Koeplinger, Kong Teck Chong et al.

    Pages 211-232

12. The Integration of Medicinal Chemistry, Drug Metabolism, and Pharmaceutical Research and Development in Drug Discovery and Development

    • Jiunn H. Lin, Drazen Ostovic, Joseph P. Vacca

    Pages 233-255

13. De Novo Design and Discovery of Cyclic HIV Protease Inhibitors Capable of Displacing the Active-Site Structural Water Molecule

    • George V. De Lucca, Prabhakar K. Jadhav, Robert E. Waltermire, Bruce J. Aungst, Susan Erickson-Viitanen, Patrick Y. S. Lam

    Pages 257-284

14. Discovery and Development of the BHAP Nonnucleoside Reverse Transcriptase Inhibitor Delavirdine Mesylate

    • Wade J. Adams, Paul A. Aristoff, Richard K. Jensen, Walter Morozowich, Donna L. Romero, William C. Schinzer et al.

    Pages 285-312

15. Famciclovir

    • Richard L. Jarvest, David Sutton, R. Anthony Vere Hodge

    Pages 313-344

16. The Use of Esters as Prodrugs for Oral Delivery of β-Lactam Antibiotics

    • Linda Mizen, George Burton

    Pages 345-365

17. Hematoregulators

    • Pradip K. Bhatnagar, William F. Huffman, Andrew G. King, Louis M. Pelus, William M. Potts, Philip L. Smith et al.

    Pages 367-391

18. Discovery and Development of GG745, a Potent Inhibitor of Both Isozymes of of 5α-Reductase

    • Stephen V. Frye, H. Neal Bramson, David J. Hermann, Frank W. Lee, Achintya K. Sinhababu, Gaochao Tian

    Pages 393-422

19. Discovery of a Potent and Selective α1A Antagonist

    • Kimberly K. Adkison, Kathy A. Halm, Joel E. Shaffer, David Drewry, Achintya K. Sinhababu, Judd Berman

    Pages 423-443

20. 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 et al.

    Pages 445-463

In the late 1980s, it became painfully evident to the pharmaceutical industry that the old paradigm of drug discovery, which involved highly segmented drug - sign and development activities, would not produce an acceptable success rate in the future. Therefore, in the early 1990s a paradigm shift occurred in which drug design and development activities became more highly integrated. This new str- egy required medicinal chemists to design drug candidates with structural f- tures that optimized pharmacological (e. g. , high affinity and specificity for the target receptor), pharmaceutical (e. g. , solubility and chemical stability), bioph- maceutical (e. g. , cell membrane permeability), and metabolic/pharmacokinetic (e. g. , metabolic stability, clearance, and protein binding) properties. Successful implementation of this strategy requires a multidisciplinary team effort, incl- ing scientists from drug design (e. g. , medicinal chemists, cell biologists, en- mologists, pharmacologists) and drug development (e. g. , analytical chemists, pharmaceutical scientists, physiologists, and molecular biologists representing the disciplines of pharmaceutics, biopharmaceutics, and pharmacokinetics/drug metabolism). With this new, highly integrated approach to drug design now widely utilized by the pharmaceutical industry, the editors of this book have provided the sci- tific community with case histories to illustrate the nature of the interdisciplinary interactions necessary to successfully implement this new approach to drug d- covery. In the first chapter, Ralph Hirschmann provides a historical perspective of why this paradigm shift in drug discovery has occurred.

• Nucleoside
• chemistry
• development
• metabolism
• pharmaceutical
• receptor

• The University of Kansas, Lawrence

  Ronald T. Borchardt

• Merck Research Laboratories, West Point

  Roger M. Freidinger

• ARIAD Pharmaceuticals, Inc., Cambridge

  Tomi K. Sawyer

• Smith Kline Beecham, Collegeville

  Philip L. Smith

Policies and ethics