Medicinal chemistry paper describes the structure-activity work that led to the discovery of anacetrapib (J Med Chem 2011)

This paper describes the structure-activity relationship studies leading to the discovery of anacetrapib, focused on varying the substitution of the oxazolidinone ring in a 5-aryloxazolidinone biphenyl-substituted scaffold of CETP inhibitors. Substituting the 4-position of the oxazolidinone ring with a methyl group in the cis-stereochemistry relative to the 5-aryl group was found to yield compounds with increased CETP inhibition potency and a robust in vivo effect of raising HDL cholesterol in transgenic mice expressing cynomolgus monkey CETP, work that directly established the chemical modifications culminating in anacetrapib itself.