We report chiral and isotopic effects on various physicochemical and in vitro biological properties: Caco-2 permeability and efflux ratio, hERG, CYP3A4 inhibition, and rat microsomal extraction ratio (ER). An internally-developed matched-pair tool, based on RDkit, identified 26691 enantiomeric pairs and 1178 isotopic pairs from the Novartis archive. The Kolmogorov�Smirnov test was used to determine the statistical significance of the chiral/isotope effects, by comparing the distributions of the property changes due to enantiomeric/isotopic modification to corresponding error distributions from differences among replicate measurements. The structural diversity of each pair set was analyzed by computing Shannon's diversity index for scaffold-based clusters. Solubility, which should not change with enantiomeric changes, served as a negative control. Two in-house biochemical assays known to be sensitive to chiral change, served as positive controls. We find that chirality has significant effect on ER but has no effect on CYP 3A4 inhibition, permeability and efflux. Isotopic change significantly affects ER. These case studies serve to provide some clarity regarding the likelihood of producing an impact to different endpoints by isotopic and chiral change in lead optimization. Cumulative distribution functions of isotopic ER differences (solid line) and replicate measurement differences (dotted line). The curves indicate that introducing deuterium can make significant changes to ER beyond measurement error. Within this date set, the success rate of such transformation is about 5% for a >50% ER change.

Chiral and isotopic matched pair identification and data analysis on physicochemical  and in vitro endpoints for drug discovery

248th National Meeting (2014)

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