Effect of Chirality on Common in Vitro Experiments: An Enantiomeric Pair Analysis

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• 作者：Jeffrey T. Bagdanoff ; Yongjin Xu ; Gavin Dollinger ; Eric Martin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：58
• 期：15
• 页码：5781-5788
• 全文大小：398K
• ISSN：1520-4804

文摘

This analysis elucidates the impact of small molecule architecture on common in vitro ADME assays. In vitro parameters considered in this analysis included Caco-2 permeability/efflux, CYP3A4 inhibition, hERG inhibition, and rat microsomal extraction ratio (ER). The statistical significance and practical meaningfulness of chirality were determined by comparison of the distribution of enantiomers with the experimental variation distribution observed from duplicate measurements. Statistical tools were applied to characterize the role of molecular architecture on the outcome of a given in vitro assay. We found that CYP3A4 inhibition, hERG inhibition, Caco-2 permeability, and efflux are unlikely to be modulated by chirality. However, rat microsomal ER provides a statistically significant, and quantitatively meaningful, chance of being influenced by chirality.