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.

Introduction; R. Hirschmann. Renin Inhibitors; S.H. Rosenberg, H.D. Kleinert. The Discovery and Development of Angiotensin II Antagonists; D.J. Carini, et al. Development of an Orally Active Tripeptide Arginal Thrombin Inhibitor; R.T. Shuman, P.D. Gesellchen. Discovery and Development of an Endothelin-A Receptor Selective Antagonist PD 156707; A.M. Doherty, A.C.G. Uprichard. Endothelin Receptor Antagonists; J.D. Elliott, et al. LHRH Antagonists; F. Haviv, et al. LHRH Agonists; K.W. Funk, et al. Discovery and Development of Somatostatin Agonists; P. Marbach, et al. Factors Impacting the Delivery of Therapeutic Levels of Pyrone-Based HIV Protease Inhibitors;; G.E. Padbury, et al. The Integration of Medicinal Chemistry, Drug Metabolism, and Pharmaceutical Research and Development in Drug Discovery and Development: The Story of Crixivan, an HIV Protease Inhibitor; J.H. Lin, et al. De Novo Design and Discovery of Cyclic HIV Protease Inhibitors Capable of Displacing the Active-Site Structural Water Molecule; G.V. De Lucca, et al. Discovery and Development of the BHAP Nonnucleoside Reverse Transcriptase Inhibitor Delaviridine Mesylate; W.J. Adams, et al. 12 Additional Chapters. Index.