Chirality in Drug Design and Synthesis

Contributors

Foreword

Introduction


1 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

References


2 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

References


3 Chirality, Drug Metabolism and Action


1 Introduction


2 Stereochemistry and Drug Disposition


3 Stereoselective Metabolism and Drug Action


4 Conclusions

References


4 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

References


5 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

References


6 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

References


7 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

References


8 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

References


9 A Practical, Enantioselective Synthesis of [R-(R*,S*)]-β-[(2-Carboxyethyl)thio]-α-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

References


10 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 α-alkylsuccinates


6 Asymmetric Synthesis of Actinonin and (—)-epiactinonin


7 Asymmetric Synthesis of Butyrolactones


8 Conclusions

Acknowledgments

References


11 Sultam-directed Asymmetric Synthesis of α-Amino Acids


1 Introduction


2 Alkylation of Glycinate Equivalents


3 Halogenation/Azide Displacement


4 Electrophilic 'Amination'


5 Conclusion

Acknowledgments

References

Appendix: Abstracts of Posters

Index