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A novel method for assessing inhibition of ibuprofen chiral inversion and its application in drug discovery.

Reddy A, Hashim M, Wang Z, Penn L, Stankovic CJ, Burdette D, Surendran N, Cai H

Preclinical Discovery-Development, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA. anita.reddy@pfizer.com

An inhibition assay to assess the potential for chiral inversion of compounds was developed using R(-)-ibuprofen as the probe substrate. Inhibition of the chiral inversion of R(-)-ibuprofen by structurally similar compounds in cyropreserved rat hepatocytes was studied using chiral HPLC and LC/MS methods for the chromatographic separation and detection of enantiomers. Concept validation of this assay was performed with three commercially available compounds and four Pfizer compounds. The results of these studies demonstrated that compounds that are structurally similar to ibuprofen inhibited the formation of S(+)-ibuprofen, suggesting that they may undergo similar enzymatic chiral inversion pathways or compete for the same enzyme active sites. Additionally, an application of this assay in early drug discovery for a specific class of compounds was demonstrated. Thirty-three in-house compounds were screened for their chiral inversion potential utilizing this assay to investigate the structure activity relationship (SAR) for this class of compounds.

Published 2 April 2007 in Int J Pharm, 335(1): 63-9.
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