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.
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.
AstraZeneca PLC, Alderley Park, Mereside, Cheshire, UK. al.dossetter@astrazeneca.com
Alexander G
AG
Dossetter
D001555:Benzene Derivatives / Q000737:chemistry*; D065100:CCR5 Receptor Antagonists; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism*; D015233:Models, Statistical; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship
D001555:Benzene Derivatives; D065100:CCR5 Receptor Antagonists; D047428:Protein Kinase Inhibitors; D019713:Receptors, CCR5; D051357:Cyclin-Dependent Kinase 2