Drug Discovery and Design
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Table of contents
- CONTENTSv
- PREFACExi
- Chapter 1. "Natural HistoryŽ Clinical Trials: An Enduring Contribution to Modern Medical Practice1
- I. Introduction1
- II. Role of the Pharmaceutical Industry in Clinical Trials2
- III. Use of Natural HistoryŽ RCTs to Validate the Cholesterol Hypothesis and Support Changes in t2
- IV. Development of a New Chemical Entity3
- V. Natural HistoryŽ RCTs: Some Considerations8
- VI. Patient Safety9
- VII. Clinical Trials and the Practice of Medicine in the Age of Genomics10
- References11
- Chapter 2. Angiotensin-Converting Enzyme Inhibitors13
- I. Introduction14
- II. Peptide Inhibitors20
- III. Captopril22
- IV. Enalapril27
- V. Lisinopril30
- VI. Fosinopril33
- VII. Clinically Available ACE Inhibitors36
- VIII. Contribution of ACE Inhibitors to the Growth of Physiological and Pathophysiological Knowledge37
- IX. Biological Advances in the Knowledge of ACE That Evolved in Parallel with the Drug Development P40
- X. Clinical Development Process of ACE Inhibitors in Hypertension41
- XI. Benefits of ACE Inhibition Beyond the Fall in Blood Pressure45
- XII. ACE Inhibitors and Congestive Heart Failure.48
- XIII. ACE Inhibitors and Myocardial Infarction49
- XIV. ACE Inhibitors, Coronary Heart Disease, and Atherosis50
- XV. ACE Inhibitors and Prevention of Restenosis52
- XVI. ACE Inhibitors and Renal Insufficiency53
- XVII. The Fallacy of the Concepts of Normotension and Hypertension and the Cardiovascular Protective54
- XVIII. Surrogate End Points in Clinical Trials of ACE Inhibition: Are We Being Misled?55
- XIX. Conclusion61
- References62
- Chapter 3. HMG-CoA Reductase Inhibitors77
- I. Background and History77
- II. Effects of Lipoproteins84
- III. Mechanisms of the Cholesterol-Lowering Effects of Reductase Inhibitors89
- IV. Combination Therapy89
- V. Safety and Tolerability91
- VI. Outcome Studies98
- VII. Mechanisms of the Reduction in Coronary Morbidity and Mortality100
- VIII. Safety of HMG-CoA Reductase Inhibitors in the Megatrials102
- IX. Future Directions105
- References108
- Chapter 4. Cyclooxygenase-2 Inhibitors115
- I. Introduction115
- II. Background116
- III. Assays for Cyclooxygenase-2 Selective Inhibitors118
- IV. Selectivity of Cyclooxygenase Inhibitors120
- V. Enzymology/Medicinal Chemistry124
- VI. Clinical Development of Cyclooxygenase-2 Inhibitors127
- VII. Future Directions133
- VIII. Conclusions135
- References137
- Chapter 5. 5α-Reductase Inhibitors143
- I. Introduction143
- II. Identification and Characterization of 5α-Reductase144
- III. Development of 5α-Reductase Inhibitors148
- IV. Clinical Studies in Men with Androgenic Disorders151
- V. Clinical Studies in Women with Androgenic Disorders169
- VI. Other 5α-Reductase Inhibitors171
- VII. Conclusion173
- References174
- Chapter 6. Peroxisome Proliferator-Activated Receptor (PPAR)γ Agonists for Diabetes181
- I. Introduction181
- II. Mechanism of Action of Peroxisome Proliferator-Activated Receptor (PPAR)γ Agonists182
- III. Clinical Experience with PPARγ Agonists195
- IV. Conclusions and Future Directions203
- References203
- Chapter 7. Discovery and Clinical Development of HIV-1 Protease Inhibitors213
- I. Introduction213
- II. Selection and Validation of HIV-1 Protease as a Therapeutic Target214
- III. Development of HIV-1 Protease Inhibitors215
- IV. Structure-Based Design216
- V. Inhibitor Identification through Broad-Based Screening223
- VI. Mechanism-Based Strategy227
- VII. Future Directions for Discovery234
- VIII. HIV-1 Protease Inhibitors: The Clinical Perspective235
- IX. Clinical Development Milestones236
- X. Issues of Ongoing Concern for the Clinical Use of HIV-1 Protease Inhibitors239
- XI. Rational Treatment Combinations That Include HIV-1 Protease Inhibitors242
- XII. Future Considerations for HIV-1 Protease Inhibitors244
- XIII. Conclusions244
- References245
- Chapter 8. Calcineurin Inhibitors and the Generalization of the Presenting Protein Strategy253
- I. Calcineurin, Calcineurin Inhibitors, and the Effects of Inhibition of Calcineurin254
- II. Inhibition by Immunophilin/Immunosuppressant Complexes: The Presenting Protein Strategy275
- III. Generalization of the Presenting Protein Strategy279
- IV. Conclusions283
- References285
- Chapter 9. Pure Selective Estrogen Receptor Modulators, New Molecules Having Absolute Cell Specifici293
- I. Introduction294
- II. Women’s Health Needs295
- III. The Estrogen Receptors and Their Multiple Gene Activation Mechanisms303
- IV. Classes of Antiestrogens.313
- V. Properties of EM-652 (SCH 57068) and EM-800 (SCH 57050)319
- References357
- Chapter 10. Monoclonal Antibody Therapy369
- I. Introduction369
- II. General Aspects of Monoclonal Antibody Therapy371
- III. Monoclonal Antibody Therapy in Organ Transplantation374
- IV. Monoclonal Antibody Therapy in Cardiac Disease376
- V. Monoclonal Antibody Therapy in Infectious Diseases379
- VI. Monoclonal Antibody Therapy in Rheumatologic and Autoimmune Diseases381
- VII. Monoclonal Antibody Therapy of Cancer387
- VIII. Conclusion403
- References404
- Chapter 11. Glucan Synthase Inhibitors as Antifungal Agents423
- I. Introduction and Background423
- II. The Fungal Cell Wall Is An Attractive Target428
- III. Early Research on Cell-Wall Active Agents430
- IV. The Pneumocandins: Mycology and Parasitology Collide437
- V. Development of Amino Compounds439
- VI. Current Compounds in Clinical Development457
- VII. Outlook466
- References466
- AUTHOR INDEX477
- SUBJECT INDEX553
Strategies to reduce medical uncertainty and build evidence have become critical to the advancement of medical knowledge and modern medical practice. As new techniques and strategies have arisen, so has the need for a current reference work. Drug Discovery and Design examines the latest research in the development of these new strategies. Some of the topics covered include angiotensin converting enzyme inhibitors, HIV protease inhibitors, PPAR agonists for diabetes, and glucan synthase antifungal agents.