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Issue 5, 2012
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Enantiomeric pairs reveal that key medicinal chemistry parameters vary more than simple physical property based models can explain

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Abstract

An on-going trend in the medicinal chemistry literature is to link physical properties of a molecule that are achiral (such as lipophilicity) to biological or pharmaceutical properties (such as pharmacokinetics and toxicity) which depend upon interactions with chiral entities. In contrast, we have explored the variation in key pharmaceutical properties between enantiomeric pairs where only the three-dimensional arrangement of atoms changes. The analysis reveals that many properties are sensitive to changes in stereochemistry and quantifies this dependence. Any variation between enantiomers cannot be explained by achiral descriptors. The analysis highlights those properties where chiral lability or measurements on racemates might be misleading and permits deductions to be made from paired experiments in which two enantiomers are studied. The analysis suggests an inherent advantage to lead optimization in a chiral series where improvement into an attractive part of chemical space might be complemented by a selection between two enantiomers with different pharmacokinetic or safety profiles. Hence, in the early stages of a drug discovery program extra preference should be given to chiral series. Surprising observations are that permeability and efflux in cell based assays are not chirally dependent whereas in vivo volume of distribution does change between enantiomers.

Graphical abstract: Enantiomeric pairs reveal that key medicinal chemistry parameters vary more than simple physical property based models can explain

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Publication details

The article was received on 19 Jan 2012, accepted on 01 Mar 2012 and first published on 27 Mar 2012


Article type: Review Article
DOI: 10.1039/C2MD20010D
Citation: Med. Chem. Commun., 2012,3, 528-540
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    Enantiomeric pairs reveal that key medicinal chemistry parameters vary more than simple physical property based models can explain

    A. G. Leach, E. A. Pilling, A. A. Rabow, S. Tomasi, N. Asaad, N. J. Buurma, A. Ballard and S. Narduolo, Med. Chem. Commun., 2012, 3, 528
    DOI: 10.1039/C2MD20010D

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