Atherosclerotic disease remains the leading cause of morbidity and mortality worldwide. In addition to high levels of LDL-C, low levels of HDL-C are also known to be a cardiovascular risk factor. Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans, and theoretically can be anti-atherosclerotic by enhancing reverse cholesterol transport, the process of cholesterol removal from peripheral tissues for delivery to the liver. In this talk, we will present lead optimization efforts which culminated in the discovery of BMS-795311.<br/><br/>BMS-795311 is a highly potent CETP inhibitor with a superior preclinical liability profile to the benchmark CETP inhibitor, torcetrapib. BMS-795311 demonstrated dose-dependent CETP inhibition in dual transgenic (CETP/ApoB-100) mice, and an equivalent increase in HDL-C, compared with torcetrapib, in hamsters. Significantly, in contrast to the off-target blood pressure increase observed with torcetrapib (occurring at 5 μM plasma exposures), no blood pressure increase was observed with BMS-795311 (30 μM plasma exposures) in rat telemetry studies. Subsequent to the termination of its development, torcetrapib was found to increase aldosterone synthase (CYP11B2) at 1 μM in vitro, independent of CETP inhibition. In contrast, BMS-795311 did not increase CYP11B2 at 10 μM. As a result, BMS-795311 was selected for advanced toxicity studies and for early clinical development.<br/>

Cholesteryl ester transfer protein inhibitor BMS-795311

249th National Meeting (2015)

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