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

Alexander G Dossetter

doi:10.1016/j.bmc.2010.04.077

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

Bioorg Med Chem. 2010 Jun 15;18(12):4405-14. doi: 10.1016/j.bmc.2010.04.077. Epub 2010 Apr 29.

Author

Alexander G Dossetter¹

Affiliation

¹ AstraZeneca PLC, Alderley Park, Mereside, Cheshire, UK. [email protected]

PMID: 20510621
DOI: 10.1016/j.bmc.2010.04.077

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.

MeSH terms

Benzene Derivatives / chemistry*
CCR5 Receptor Antagonists
Cyclin-Dependent Kinase 2 / antagonists & inhibitors
Cyclin-Dependent Kinase 2 / metabolism
Databases, Factual
Drug Design
Humans
Microsomes, Liver / metabolism*
Models, Statistical*
Protein Kinase Inhibitors / chemistry
Receptors, CCR5 / metabolism
Structure-Activity Relationship

Substances

Benzene Derivatives
CCR5 Receptor Antagonists
Protein Kinase Inhibitors
Receptors, CCR5
Cyclin-Dependent Kinase 2