A matched molecular pair analysis of in vitro human microsomal metabolic stability measurements for heterocyclic replacements of di-substituted benzene containing compounds – identification of those isosteres more likely to have beneficial effects

Abstract

A matched molecular pair analysis (MMPA) was used to study the classic medicinal chemistry transformation of a di-substituted benzene into a heterocyclic ring. Matched pairs were identified for 45 heterocyclic transforms (5 and 6 membered rings) and in vitro human microsomal stability analysed. Of these, 12 transforms showed significant beneficial increase in stability, suggesting these heterocycles as preferred changes during compound optimisation.