Chirality in Drug Research

by Francotte, Eric; Lindner, Wolfgang; Mannhold, Raimund; Kubinyi, Hugo; Folkers, Gerd

• ISBN13: 9783527310760
• ISBN10: 3527310762
• Edition: 1st
• Format: Hardcover
• Copyright: 2006-11-10
• Publisher: Wiley-VCH

Summary

Divided into the three main sections of synthesis, analysis and drug development, this handbook covers all stages of the drug development process, including large-scale synthesis and purification of chirally pure pharmaceuticals. The two editors from academia and a major pharmaceutical company have assembled an experienced, international team who provide first-hand practical advice and report previously unpublished data.In the first section, the isolation of chiral drugs from natural sources, their production in enzymatic processes and the resolution of racemic mixtures in preparative chromatography are outlined in separate chapters. For the section on qualitative and quantitative analysis, enantioselective chromatographic methods are presented as well as optical methods and CE-MS, while the final section deals with the pharmacology, pharmacokinetics and metabolic aspects of chiral drugs, devoting whole chapters to stereoselective drug binding and modeling chiral drug-receptor interactions.With its unique industry-relevant aspects, this is a must for medicinal and pharmaceutical chemists.

Author Biography

Eric Francotte received his BS and PhD degrees from the University of Louvain (Belgium). After postdoctoral work at the University of Geneva, he joined the Central Research Laboratories at Ciba-Geigy, where he was working on optically active polymers. He is now Director and Head of Separations at the Novartis Institutes for BioMedical Research in Basel (Switzerland). He is also an editor of the Wiley journal ?Chirality?. His major interests include development and applications of chiral stationary phases for the separation of stereoisomers on an analytical and preparative scale. <br> <br> Wolfgang Lindner received his PhD degree in Organic Chemistry from the University of Graz (Austria). After several academic positions, including a period at the FDA in Bethesda (USA), he was appointed the chair in Analytical Chemistry at the University of Vienna (Austria). He is also the editor of the Journal of Chromatography B, and the current president of the Austrian Society of Analytical Chemistry. His major interests lie in enantioselective separation techniques, including LC, CE, membranes, extractions, and in stereoselective pharmacokinetics.<br>

Table of Contents

Preface.

List of Contributors.

Introduction.

1 Chiral Drugs from a Historical Point of View (Joseph Gal).

1.1 Introduction.

1.2 AWord About Words.

1.3 Old Chiral Drugs: Natural Remedies 3000BC–1900.

1.4 Recognition of Chirality in Drugs.

1.5 Enantioselectivity in Drug Action and Drug Metabolism: The Beginnings.

1.6 Drug Chirality in the 20th Century.

References.

Synthesis.

2 Stereoselective Synthesis of Drugs – An Industrial Perspective (Hans-Jürgen Federsel).

2.1 Introduction: Historical Overview.

2.2 Asymmetry from an Industrial Scale Perspective.

2.3 Stereoselective Processes in Drug Manufacture – Drivers and Blockers.

2.4 The Metal – Friend and Foe.

2.5 Ligand Development – At the Core of Catalytic Chemistry.

2.6 Asymmetric Reactions – A Rich Reservoir.

2.7 Retrospect and Prospect.

References.

3 Aspects of Chirality in Natural Products Drug Discovery (Philipp Krastel, Frank Petersen, Silvio Roggo, Esther Schmitt, and Ansgar Schuffenhauer).

3.1 Introduction.

3.2 Stereochemical Aspects of Natural Products.

3.3 Mechanisms of Stereochemical Control in Natural Product Biosynthesis.

3.4 Biological Activity of Natural Products Related to Stereochemistry.

References.

4 Biotransformation Methods for Preparing Chiral Drugs and Drug Intermediates (Michael Müller and Marcel Wubbolts).

4.1 Introduction.

4.2 Examples of Established Applications of Biocatalysts in the Synthesis of Pharmaceuticals.

4.3 Some Special Aspects of Biocatalysts, Recent Developments.

4.4 Conclusions and Outlook.

References.

Separations.

5 Resolution of Chiral Drugs and Drug Intermediates by Crystallisation (Kazuhiko Saigo).

5.1 Introduction.

5.2 Physical Enantioseparation – Preferential Crystallization.

5.3 Chemical Enantioseparation – Diastereomeric Salt Formation.

5.4 The Bridge Between Preferential Crystallization and Diastereomeric Salt Formation.

5.5 Process Research on the Enantioseparation of Racemates by Diastereomeric Salt Formation.

5.6 Examples of Enantioseparations in the Pharmaceutical Industry.

References.

6 Isolation and Production of Optically Pure Drugs by Enantioselective Chromatography (Eric Francotte).

6.1 Introduction.

6.2 General Considerations Regarding the Preparation of Single Stereoisomers of Chiral Drugs.

6.3 Preparative Chiral Stationary Phases.

6.4 Strategies for Performing Enantioselective Separations.

6.5 Preparative Enantioselective Resolution of Chiral Drugs.

6.6 Conclusion.

References.

7 Stereoselective Chromatographic Methods for Drug Analysis (Norbert M. Maier and Wolfgang Lindner).

7.1 Introduction.

7.2 The Role of Enantioselective Analysis in Drug Development.

7.3 Separation Techniques in Enantiomer Analysis.

7.4 Principle of Enantiomer Separation.

7.5 Molecular Requirements for Chiral Recognition.

7.6 Thermodynamic Principles of Enantiomer Separation.

7.7 Role of Mobile Phase in Enantiomer Separation.

7.8 Chiral Selectors and Chiral Stationary Phases Employed in Liquid Chromatographic Enantiomer Separation.

7.9 Conclusions.

References.

8 Capillary Electrophoresis Coupled to Mass Spectrometry for Chiral Drugs Analysis (Serge Rudaz and Jean-Luc Veuthey).

8.1 Introduction.

8.2 Capillary Electrophoresis (CE).

8.3 CE-MS Coupling.

8.4 Chiral Separation Strategies.

8.5 Partial Filling.

8.6 Partial Filling – Counter Current Technique.

8.7 Chiral Micellar Electrokinetic Chromatography.

8.8 Quantitative Aspects in CE-MS and Parameters for CE-ESI-MS Coupling.

8.9 Capillary Electrochromatography Coupled to Mass Spectrometry.

8.10 Discussion and Conclusion.

References.

9 Powerful Chiral Molecular Tools for Preparation of Enantiopure Alcohols and Simultaneous Determination of Their Absolute Configurations by X-Ray Crystallography and/or 1H NMR Anisotropy Methods (Nobuyuki Harada).

9.1 Introduction.

9.2 Methodologies for Determining Absolute Configuration.

9.3 CSDP Acid, Camphorsultam Dichlorophthalic Acid (–)-1, Useful for the Enantioresolution of Alcohols by HPLC and Simultaneous Determination of Their Absolute Configurations by X-ray Crystallography 287

9.4 A Novel Chiral Molecular Tool, 2-Methoxy-2-(1-naphthyl)propionic Acid (MαNP Acid (S)-(+)-3), Useful for Enantioresolution of Alcohols and Simultaneous Determination of Their Absolute Configurations by the ¹H NMR Aisotropy Method.

9.5 Absolute Configuration of the Thyroid Hormone Analog KAT-2003 as Determined by the 1H NMR Anisotropy Method with MαNP Acid.

9.6 Conclusion.

References.

10 Keywords in Chirality Modeling Molecular Modeling of Chirality – Software and Literature Research on Chirality in Modeling, Chirality in Docking, Chiral Ligand–Receptor Interaction and Symmetry (Gerd Folkers, Mine Yarim, and Pavel Pospisil).

10.1 Introduction.

10.2 Chirality in QSAR.

10.3 Molecular Modeling in Chiral Chromatography.

10.4 Chirality of Protein Residues, Homology Modeling.

10.5 Chiral Selective Binding, MDS methods.

10.6 Docking of Chiral Compounds.

10.7 Molecular Modeling Software Dealing with Chirality and Some References to Its Successful Application.

References.

Subject Index.