Chirality in Drug Design and Synthesis

ContributorsForewordIntroduction1 Chirality: Pharmacological Action and Drug Development 1 Introduction 2 Terminology 3 Enantioselectivity in Pharmacological Activity 4 Enantioselectivity in Pharmacodynamics Resulting from Differences in the Pharmacokinetics of the Enantiomers 5 Conclusion References2 Racemic Therapeutics: Problems all Along the Line 1 Introduction 2 Implications of Chirality in Bioactive Agents 3 Clinical Pharmacology of Racemic Therapeutics 4 Ethical Aspects of Drug Development, Evaluation and Use 5 Noninformation and Disinformation in the Field of Chirality 6 Racemates as Drug Combinations 7 Perspectives 8 Summary References3 Chirality, Drug Metabolism and Action 1 Introduction 2 Stereochemistry and Drug Disposition 3 Stereoselective Metabolism and Drug Action 4 Conclusions References4 From Enzyme Mimics to Molecular Self-Assembly Processes 1 Introduction 2 A Gift from Nature 3 Needs of Enzyme Mimics 4 Serendipity Yet Again 5 A Chiral Crown Ether as a Reagent 6 The Same Chiral Crown Ether as a Catalyst 7 Coordination Through the Second Sphere 8 Planned Molecular Self-Assembly 9 From Host-Guest Chemistry to Molecular Assemblies 10 Structure-Directed Synthesis 11 The Future Acknowledgments References5 Modeling of Drug-Receptor Interactions: Stereoselectivity of 5-Hydroxytryptamine and Dopamine Receptors in the Brain 1 Introduction 2 Interactions Between L-ZGP and 8-OH DPAT 3 Modeling of Drug-Receptor Interactions 4 DA D2-Receptor Agonists and Antagonists 5 5-HT1A-Receptor Agonists and Antagonists Acknowledgments References6 Molecular Basis of the Activity of Antibiotics of the Vancomycin Group: Guides for Peptide-Peptide Binding 1 Introduction 2 Stereoselectivity 3 Peptide-Peptide Molecular Recognition 4 Approximate Binding Constants Estimated for Simple Carboxylic Acids 5 A Molecular Interpretation of the Binding Process Acknowledgments References7 Recent Developments in the Use of Enzyme-catalysed Reactions in Organic Synthesis 1 Introduction 2 Recent Uses of Hydrolase Enzymes 3 Recent Uses of Oxidoreductase Enzymes 4 Enzyme-Catalysed Reactions Resulting in the Formation of Carbon-Carbon Bonds 5 Future Developments in the Area of Biotransformations References8 Recent Progress in Research on the Immunosuppressant FK-506 1 Isolation, Structure Determination and Stability of FK-506 2 Biological Activity 3 Synthetic Approaches to FK-506 References9 A Practical, Enantioselective Synthesis of [R-(R*,S*)]-ß-[(2-Carboxyethyl)thio]-a-hydroxy-2-(8-phenyloctyl)-benzenepropanoic acid (SK&F 104353), a Potent LTD4 Antagonist 1 Introduction 2 Background 3 Improvements in the Synthesis of 2-(phenyloctyl)benzaldehyde 4 Regioselective Epoxide Opening 5 Enantioselective Synthesis of an Epoxide Intermediate 6 Final Elaboration of SK&F 104353 Acknowledgments References10 Chirality Recognition in Synthesis 1 Introduction 2 Structure of the Chiral Iron Acetyl Complex [(C5H5)Fe(CO)(PPh3)COCH3] 3 Stereoselective Enolate Alkylation Reactions 4 Asymmetric Synthesis of Captopril and Epicaptopril 5 Asymmetric Synthesis of Differentially Protected a-alkylsuccinates 6 Asymmetric Synthesis of Actinonin and (-)-epiactinonin 7 Asymmetric Synthesis of Butyrolactones 8 Conclusions Acknowledgments References11 Sultam-directed Asymmetric Synthesis of a-Amino Acids 1 Introduction 2 Alkylation of Glycinate Equivalents 3 Halogenation/Azide Displacement 4 Electrophilic 'Amination' 5 Conclusion Acknowledgments ReferencesAppendix: Abstracts of PostersIndex