Table of Contents

Note continued: References.
13.1. Introduction.
13.2. The Target Enzyme: HIV-1 Aspartic Acid Protease.
13.3. Advent of Protease Inhibitors, HAART, and Structural Insights from S aquinavir.
13.4. Cyclic Ethers to Mimic Peptide Bonds: Inspiration from Natural Products.
13.5. Design of Conceptually New Cyclic Ether-derived Ligands and Corresponding Protease Inhibitors.
13.5.1. Exploration of ligands from cyclic ethers to cyclic sulfones.
13.5.2. Design and development of bicyclic bis-tetrahydrofuran (bis-THF) ligand.
13.6. Design Strategy to Combat Drug Resistance by Targeting Protein Backbone: 'Backbone Binding Concept'.
13.7. Design of PIs Promoting Strong Backbone Interactions from S2 to S2 Subsites.
13.8. The 'Backbone Binding Concept' and Its Relevance to Combat Drug Resistance.
13.9. Selection of Darunavir as a Promising Drug Candidate.
13.9.1. Thermodynamic and kinetic effects behind darunavir's high binding affinity for the protease.
13.9.2. Darunavir inhibits HIV-1 protease dimerization: a unique dual mode of action.
13.10. Convenient Syntheses of the bis-THF Ligand.
13.11. Clinical Use of Darunavir in the Management of HIV-1 Infection.
13.12. Design of Potent Inhibitors Targeting the Protease Backbone.
13.13. Conclusion.
14.1. The Story of anti-TNF: From Septic Shock to Inflammatory Diseases.
14.2. From a Clinically Validated Target to the Design of anti-TNF Biopharmaceuticals.
14.2.1. Development of anti-TNF-cc mAbs.
14.2.2. Development of soluble receptors.
14.3. Marketing Approvals and Post-Marketing Clinical Experience.
14.3.1. Efficacy (biomarkers and sequential treatment).
14.3.2. Tolerance.
14.4. Structure-Clinical Activities Relationships Drawn from the Clinical Experience.
14.4.1. Immunogenicity.
14.4.2.mAbs, granulomas, and membrane TNF.
14.5. Conclusions.
15.1. Introduction.
15.2. Past Approaches to Lowering Levels of Circulating Cholesterol.
15.2.1. Bile acid sequestrants.
15.2.2. Hypocholesterolaemic drugs.
15.2.3. Inhibition of cholesterol absorption by fibrates: inhibitors of ACAT.
15.2.4. Statins: inhibitors of HMG-CoA reductase.
15.2.5. Inhibition of cholesterol absorption by saponins.
15.3. Further Work on ACAT Inhibitors.
15.4. Inhibition of a Novel Mechanism for Cholesterol Uptake and the Discovery of SCH 48461.
15.5. Design of Ezetimibe (SCH 58235).
15.6. Ezetimibe in Human Studies.
15.7. Identification of a New Mechanism for Cholesterol Uptake.
15.8. Conclusion.
References. The fundamental concept of the book is to provide, for the first time, an introduction to understand the science behind successful pharmaceutical research and development programs. As well as explaining the basic principles, the book compares and contrasts approaches to both biopharmaceuticals (proteins) and small molecule drugs and presents an overview of the business and management issues for these approaches. The second part of the book provides 9 carefully selected real life case studies to illustrate how the theory presented in the first part of the book is actually being put into practice. Introduction to Biological and Small Molecule Drug Research and Development is intended for late-stage undergraduates or postgraduates studying chemistry (at the biology interface), biochemistry, medicine, pharmacy, medicine or allied subjects. The book would be used as part of the reading matter for a wide variety of science degree courses, in post-graduate taught material (Masters and PhD) and as basic background reading for scientists in the pharmaceutical industry. . For the first time the fundamental principles of the science of biopharmaceutics and small molecule chemotherapeutics are discussed side-by-side at a basic level . Edited by three senior scientists with over 100 years experience in drug research who have compiled the best scientific comparison of small molecule and biopharmaceuticals approaches to new drugs . The book will be of broad interest to students of medicine, pharmacy, biochemistry and chemistry who wish to learn about drug discovery . Illustrated with key examples of important drugs that exemplify the basic principles of pharmaceutical drug research and development.