A statistical analysis of in vitro human microsomal metabolic stability of small phenyl group substituents, leading to improved design sets for parallel SAR exploration of a chemical series.

ABSTRACT

An analysis of in vitro human liver microsomal turnover assay results from a large dataset ( approximately 75 K) of experimental compounds tested is presented. Combined with an analysis of small (<6 Ha) substituents on known drugs and existing published results a new set of 29 substituents (consensus) is proposed to increase stability and probe SAR (an enhanced 'Topliss set'). In addition a different group of 28 substituents are identified as unlikely to change in vitro HLM stability, and a further set of compounds focuses on increasing HLM stability only.