Drug Discovery and Design

Preface."Natural History" Clinical Trials: An Enduring Contribution to Modern Medical Practice, E.M. Scolnick, E.E. Slater, and G.W. Williams:Introduction.Role of the Pharmaceutical Industry in Clinical Trials.Use of "Natural History" RCTs to Validate the Cholesterol Hypothesis and Support Changes in the Management of Other Conditions.Development of a New Chemical Entity."Natural History" RCTs: Some Considerations.Patient Safety.Clinical Trials and the Practice of Medicine in the Age of Genomics.Angiotensin-Converting Enzyme Inhibitors, J. Menard and A. Patchett:Introduction.Peptide Inhibitors.Captopril.Enalapril.Lisinopril.Fosinopril.Clinically Available ACE Inhibitors.Contribution of ACE Inhibitors to the Growth of Physiological and Pathophysiological Knowledge.Biological Advances in the Knowledge of ACE That Evolved in Parallel with the Drug Development Process.Clinical Development Process of ACE Inhibitors in Hypertension.Benefits of ACE Inhibition Beyond the Fall in Blood Pressure.ACE Inhibitors and Congestive Heart Failure.ACE Inhibitors and Myocardial Infarction.ACE Inhibitors, Coronary Heart Disease, and Atherosis.ACE Inhibitors and Prevention of Restenosis.ACE Inhibitors and Renal Insufficiency.The Fallacy of the Concepts of Normotension and Hypertension and the Cardiovascular Protective Effects of ACE Inhibitors.Surrogate End Points in Clinical Trials of ACE Inhibition: Are We Being Misled?Conclusion.HMG-CoA Reductase Inhibitors, R. Illingworth and J.A. Tolbert:Background and History.Effects of Lipoproteins.Mechanisms of the Cholesterol-Lowering Effects of Reductase Inhibitors.Combination Therapy.Safety and Tolerability.Outcome Studies.Mechanisms of the Reduction in Coronary Morbidity and Mortality.Safety of HMG-CoA Reductase Inhibitors in the Megatrials.Future Directions.Cyclooxygenase-2 Inhibitors, A.S. Nies:Introduction.Background.Assays for Cyclooxygenase-2 Selective Inhibitors.Selectivity of Cyclooxygenase Inhibitors.Enzymology/Medicinal Chemistry.Clinical Development of Cyclooxygenase-2 Inhibitors.Future Directions.Conclusions.5a-Reductase Inhibitors, J.D. McConnell and E. Stoner:Introduction.Identification and Characterization of 5a-Reductase.Development of 5a-Reductase Inhibitors.Clinical Studies in Men with Androgenic Disorders.Clinical Studies in Women with Androgenic Disorders.Other 5a-Reductase Inhibitors.Conclusion.Peroxisome Proliferator-Activated Receptor (PPAR) ¿ Agonists for Diabetes, D.E. Moller and D.A. Greene:Introduction.Mechanism of Action of Peroxisome Proliferator-Activated Receptor (PPAR) ¿ Agonists.Clinical Experience with PPAR¿ Agonists.Conclusions and Future Directions.Discovery and Clinical Development of HIV-1 Protease Inhibitors, J. Huff and J. Kahn:Introduction.Selection and Validation of HIV-1 Protease as a Therapeutic Target.Development of HIV-1 Protease Inhibitors.Structure-Based Design.Inhibitor Identification through Broad-Based Screening.Mechanism-Based Strategy.Future Directions for Discovery.HIV-1 Protease Inhibitors: The Clinical Perspective.Clinical Development Milestones.Issues of Ongoing Concern for the Clinical Use of HIV-1 Protease Inhibitors.Rational Treatment Combinations That Include HIV-1 Protease Inhibitors.Future Considerations for HIV-1 Protease Inhibitors.Conclusions.Calcineurin Inhibitors and the Generalization of the Presenting Protein Strategy, K.W. Vogel, R. Briesewitz, T.J. Wandless, and G.R. Crabtree:Calcineurin, Calcineurin Inhibitors, and the Effects of Inhibition of Calcineurin.Inhibition by Immunophilin/Immunosuppressant Complexes: The Presenting Protein Strategy.Generalization of the Presenting Protein Strategy.Conclusions.Pure Selective Estrogen Receptor Modulators, New Molecules Having Absolute Cell Specificity Ranging from Pure Antiesotrogenic to Complete Estrogen-Like Activities, F. Labrie, C. Labrie, A. Bélanger, V. Giguere, J. Simard, Y. Mérand, S. Gauthier, V. Luu-The, B. Candas, C. Martel, and S. Luo:Introduction.Women's Health Needs.