Chirality pharmacology

Caldwell, J., (1995) Regulation of Chiral Drugs, Pharmaceutical News, 2, 22-23. Caldwell, J. (1995) Chiral Pharmacology and the Regulation of New Drugs, Chem. and Industry, 5, 176-179. 

Hyneck, M. Dent, J. Hook, J. Chirality pharmacological action and drug development. In Chirality in Drug Design and Synthesis, Brown, C., Ed. Academic Press San Diego, 1990 1-28. 

By the end of the 19th century, despite hmitations in the elucidation of complex organic structures, many chiral pharmacologically active compounds became available, often in both enantiomeric forms. This in turn led to studies comparing the enantiomers for their pharmacological actions and biological fate. 

The Cahn-Ingold-Prelog (CIP) rules stand as the official way to specify chirahty of molecular structures [35, 36] (see also Section 2.8), but can we measure the chirality of a chiral molecule. Can one say that one structure is more chiral than another. These questions are associated in a chemist s mind with some of the experimentally observed properties of chiral compounds. For example, the racemic mixture of one pail of specific enantiomers may be more clearly separated in a given chiral chromatographic system than the racemic mixture of another compound. Or, the difference in pharmacological properties for a particular pair of enantiomers may be greater than for another pair. Or, one chiral compound may rotate the plane of polarized light more than another. Several theoretical quantitative measures of chirality have been developed and have been reviewed elsewhere [37-40]. 

It was apparent that the FDA recognized the ability of the pharmaceutical industry to develop chiral assays. With the advent of chiral stationary phases (CSPs) in the early 1980s [8, 9], the tools required to resolve enantiomers were entrenched, thus enabling the researcher the ability to quantify, characterize, and identify stereoisomers. Given these tools, the researcher can assess the pharmacology or toxicology and pharmacokinetic properties of enantiopure drugs for potential interconversion, absorption, distribution, and excretion of the individual enantiomers. 

Enantiomers have identical chemical properties, except when they react with other chiral compounds. Because many biochemical substances are chiral, one consequence of this difference in reactivity is that enantiomers may have different odors and pharmacological activities. The molecule has to fit into a cavity, or slot, of a certain shape, either in an odor receptor in the nose or in an enzyme. Only one member of the enantiomeric pair may be able to fit. 

Enantiomer A molecule with a chiral centre (asymmetric carbon atom) existing as two isomers designated D and L that may have different physiological or pharmacological activities. 

The enantioselective reduction of unsaturated alcohol derivatives has been applied to the synthesis of several biologically active compounds (Scheme 24.12). Warfarin (123, R=H) is an important anticoagulant that is normally prescribed as the racemate, despite the enantiomers having dissimilar pharmacological profiles. One of the earliest reported uses of DuPhos was in the development of a chiral switch for this bioactive molecule, facilitating the preparation of (R)- and (S)-warfarin [184]. Although attempted reduction of the parent hydroxycoumarin 122 (R=H) led to formation of an unreactive cyclic hemiketal, hydrogenation of the sodium salt proceeded smoothly with Rh-Et-DuPhos in 86-89% ee. 

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