Christopher F. Thompson

Biphenyl-Substituted Oxazolidinones as Cholesteryl Ester Transfer Protein Inhibitors: Modifications of the Oxazolidinone Ring Leading to the Discovery of Anacetrapib

The development of the structure-activity studies leading to the discovery of anacetrapib is described. These studies focused on varying the substitution of the oxazolidinone ring of the 5-aryloxazolidinone system. Specifically, it was found that substitution of the 4-position with a methyl group with the cis-stereochemistry relative to the 5-aryl group afforded compounds with increased cholesteryl ester transfer protein (CETP) inhibition potency and a robust in vivo effect on increasing HDL-C levels in transgenic mice expressing cynomolgus monkey CETP.

Discovery of Substituted Biphenyl Oxazolidinone Inhibitors of Cholesteryl Ester Transfer Protein

Recently, there has been a strong interest in the ability to increase levels of high density lipoprotein-cholesterol (HDL-C). This interest stems from the hypothesis that such an elevation in HDL-C will decrease the likelihood of cardiovascular disease. Inhibition of cholesteryl ester transfer protein (CETP) has been shown to elevate HDL-C levels in human subjects. This letter describes the discovery of a novel and potent (<100 nM IC50 for the inhibition of CE transfer) CETP inhibitor scaffold containing an oxazolidinone core.