anacetrapib and Dyslipidemias

Cholesteryl ester transfer protein (CETP) inhibitors reduce the transfer of cholesteryl esters from the high-density lipoprotein (HDL-C) to apolipoprotein such as VLDL/LDL, with exchange of triglycerides. Thus, this inhibition increases the HDL-C levels, which is believed to lower the risk for heart disease and stroke. We report here a series of CETP inhibitors based on the cyclic, bicyclic urea and sulfamide cores. These CETP inhibitors exemplified by 15, 31, and 45 demonstrated in vitro potency in inhibiting the CETP transfer activity, and 15, 31 showing in vivo efficacy to increase HDL-C levels in cynomolgus-CETP transgenic mice. The synthesis and biological evaluations of these CETP inhibitors are described.

Topics: Animals; Anticholesteremic Agents; Bridged Bicyclo Compounds; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cyclization; Dyslipidemias; Humans; Mice; Mice, Transgenic; Structure-Activity Relationship; Sulfonamides; Urea