Torcetrapib
A conformationally constrained CETP inhibitor matches the HDL-raising efficacy of torcetrapib across hamsters, transgenic mice, and monkeys (J Med Chem 2009)
Original title: Design, synthesis, and biological evaluation of (2R,alphaS)-3,4-dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)-phenyl]-alpha-(trifluoromethyl)-1(2H)-quinolineethanol as potent and orally active cholesteryl ester transfer protein inhibitor
Seeking a CETP inhibitor combining high in vitro potency with optimal in vivo efficacy, researchers designed a conformationally constrained molecule based on a highly potent but flexible earlier compound, leading to the discovery of a potent and selective quinoline-based inhibitor. Tested across three different in vivo models of HDL raising, high-fat fed hamsters, human CETP transgenic mice, and cynomolgus monkeys, the efficacy of the new compound for raising HDL cholesterol was found to be comparable to torcetrapib, supporting conformational constraint as a viable medicinal chemistry strategy for optimizing this class of CETP inhibitors.
Original abstract
With the goal of identifying a CETP inhibitor with high in vitro potency and optimal in vivo efficacy, a conformationally constrained molecule was designed based on the highly potent and flexible 13. The synthetic chemistry efforts led to the discovery of the potent and selective 12. In high-fat fed hamsters, human CETP transgenic mice, and cynomolgus monkeys, the in vivo efficacy of 12 for raising HDL-C was demonstrated to be comparable to torcetrapib.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.