El. knyga: Drug Discovery and Design

Preface xi ``Natural History Clinical Trails: An Enduring Contribution to Modern Medical Practice Edward M. Scolnick Eve E. Slater George W. Williams Introduction 1(1) Role of the Pharmaceutical Industry in Clinical Trials 2(1) Use of ``Natural History RCTs to Validate the Cholesterol Hypothesis and Support Changes in the Management of Other Conditions 2(1) Development of a New Chemical Entity 3(5) ``Natural History RCTs: Some Considerations 8(1) Patient Safety 9(1) Clinical Trials and the Practice of Medicine in the Age of Genomics 10(4) References 11(3) Angiotensin-Converting Enzyme Inhibitors Joel Menard Arthur Patchett Introduction 14(6) Peptide Inhibitors 20(2) Captopril 22(5) Enalapril 27(3) Lisinopril 30(3) Fosinopril 33(3) Clinically Available ACE Inhibitors 36(1) Contribution of ACE Inhibitors to the Growth of Physiological and Pathophysiological Knowledge 37(3) Biological Advances in the Knowledge of ACE That Evolved in Parallel with the Drug Development Process 40(1) Clinical Development Process of ACE Inhibitors in Hypertension 41(4) Benefits of ACE Inhibition Beyond the Fall in Blood Pressure 45(3) ACE Inhibitors and Congestive Heart Failure 48(1) ACE Inhibitors and Myocardial Infarction 49(1) ACE Inhibitors, Coronary Heart Disease, and Atherosis 50(2) ACE Inhibitors and Prevention of Restenosis 52(1) ACE Inhibitors and Renal Insufficiency 53(1) The Fallacy of the Concepts of Normotension and Hypertension and the Cardiovascular Protective Effects of ACE Inhibitors 54(1) Surrogate End Points in Clinical Trials of ACE Inhibition: Are We Being Misled? 55(6) Conclusion 61(16) References 62(15) HMG-CoA Reductase Inhibitors Roger Illingworth Jonathan A. Tolbert Background and History 77(7) Effects of Lipoproteins 84(5) Mechanisms of the Cholesterol-Lowering Effects of Reductase Inhibitors 89(1) Combination Therapy 89(2) Safety and Tolerability 91(7) Outcome Studies 98(2) Mechanisms of the Reduction in Coronary Morbidity and Mortality 100(2) Safety of HMG-CoA Reductase Inhibitors in the Megatrials 102(3) Future Directions 105(10) References 108(7) Cyclooxygenase-2 Inhibitors Alan S. Nies Introduction 115(1) Background 116(2) Assays for Cyclooxygenase-2 Selective Inhibitors 118(2) Selectivity of Cyclooxygenase Inhibitors 120(4) Enzymology/Medicinal Chemistry 124(3) Clinical Development of Cyclooxygenase-2 Inhibitors 127(6) Future Directions 133(2) Conclusions 135(8) References 137(6) 5α-Reductase Inhibitors John D. McConnell Elizabeth Stoner Introduction 143(1) Identification and Characterization of 5α-Reductase 144(4) Development of 5α-Reductase Inhibitors 148(3) Clinical Studies in Men with Androgenic Disorders 151(18) Clinical Studies in Women with Androgenic Disorders 169(2) Other 5α-Reductase Inhibitors 171(2) Conclusion 173(8) References 174(7) Peroxisome Proliferator-Activated Receptor (PPAR)γ Agonists for Diabetes David E. Moller Douglas A. Greene Introduction 181(1) Mechanism of Action of Peroxisome Proliferator-Activated Receptor (PPAR)γ Agonists 182(13) Clinical Experience with PPARγ Agonists 195(8) Conclusions and Future Directions 203(1) References 203(10) Discovery and Clinical Development of HIV-1 Protease Inhibitors Joel Huff James Kahn Introduction 213(1) Selection and Validation of HIV-1 Protease as a Therapeutic Target 214(1) Development of HIV-1 Protease Inhibitors 215(1) Structure-Based Design 216(11) Inhibitor Identification through Broad-Based Screening Mechanism-Based Strategy 227(7) Future Directions for Discovery 234(2) HIV-1 Protease Inhibitors: The Clinical Perspective 235(1) Clinical Development Milestones 236(3) Issues of Ongoing Concern for the Clinical Use of HIV-1 Protease Inhibitors 239(3) Rational Treatment Combinations That Include HIV-1 Protease Inhibitors 242(2) Future Considerations for HIV-1 Protease Inhibitors 244(1) Conclusions 244(10) References 245(9) Calcineurin Inhibitors and the Generalization of the Presenting Protein Strategy Kurt W. Vogel Roger Briesewitz Thomas J. Wandless Gerald R. Crabtree Calcineurin, Calcineurin Inhibitors, and the Effects of Inhibition of Calcineurin 254(21) Inhibition by Immunophilin/Immunosuppressant Complexes: The Presenting Protein Strategy 275(4) Generalization of the Presenting Protein Strategy 279(4) Conclusions 283(11) References 285(9) Pure Selective Estrogen Receptor Modulators, New Molecules Having Absolute Cell Specificity Ranging from Pure Antiestrogenic to Complete Estrogen-Like Activities Fernand Labrie Claude Labrie Alain Belanger Vincent Giguere Jacques Simard Yves Merand Sylvain Gauthier Van Luu-The Bernard Candas Celine Martel Shouqi Luo Introduction 294(1) Womens Health Needs 295(8) The Estrogen Receptors and Their Multiple Gene Activation Mechanisms 303(10) Classes of Antiestrogens 313(6) Properties of EM-652 (SCH 57068) and EM-800 (SCH 57050) 319(50) References 357(12) Monoclonal Antibody Therapy John W. Park Josef Smolen Introduction 369(2) General Aspects of Monoclonal Antibody Therapy 371(3) Monoclonal Antibody Therapy in Organ Transplantation 374(2) Monoclonal Antibody Therapy in Cardiac Disease 376(3) Monoclonal Antibody Therapy in Infectious Diseases 379(2) Monoclonal Antibody Therapy in Rheumatologic and Autoimmune Diseases 381(6) Monoclonal Antibody Therapy of Cancer 387(16) Conclusion 403(20) References 404(19) Glucan Synthase Inhibitors as Antifungal Agents Myra B. Kurtz John H. Rex Introduction and Background 423(5) The Fungal Cell Wall Is An Attractive Target 428(2) Early Research on Cell-Wall Active Agents 430(7) The Pneumocandins: Mycology and Parasitology Collide 437(2) Development of Amino Compounds 439(18) Current Compounds in Clinical Development 457(9) Outlook 466(11) References 466(11) Author Index 477(76) Subject Index 553