A new cycloalkene-scaffold CETP inhibitor raises HDL cholesterol in hamsters (Eur J Med Chem 2016)

Original title: Design, synthesis and biological evaluation of novel cholesteryl ester transfer protein inhibitors bearing a cycloalkene scaffold

Eur J Med Chem · 27 July 2016 · 4

Liu C, Luo C, Hao L, Wu Q, Xie H, Zhao S, Hao C, Zhao D, Cheng M

Based on the structure of Merck's biphenyl CETP inhibitor, researchers designed a novel N,N-substituted-cycloalkenyl-methylamine scaffold using core-replacement and conformational-restriction strategies, synthesising twenty-eight compounds and testing their CETP inhibitory activity. Structure-activity relationship studies showed polar substituents were tolerated at one position while hydrophobic alkyl groups at the 5-position of the cyclohexene ring were critical for potency. Compound 17a, bearing an N-(5-pyrazolyl-pyrimidin-2-yl)-cycloalkenyl-methylamine scaffold, showed excellent CETP inhibitory activity in vitro (IC50 equals 0.07 micromolar), an acceptable pharmacokinetic profile in rats, and efficiently raised HDL cholesterol in high-fat-fed hamsters.

Original abstract

Cholesteryl ester transfer protein (CETP) is a potential target for cardiovascular disease therapy as inhibition of CETP leads to increased HDL-C in humans. Based on the structure of Merck's biphenyl CETP inhibitor, we designed novel N,N-substituted-cycloalkenyl-methylamine scaffold derivatives by utilizing core replacement and conformational restriction strategies. Consequently, twenty-eight compounds were synthesized and evaluated for their inhibitory activity against CETP. Their preliminary structure-activity relationships (SARs) studies indicate that polar substituents were tolerated in moiety A and hydrophobic alkyl groups at the 5-position of cyclohexene were critical for potency. Among them, compound 17a, bearing an N-(5-pyrazolyl-pyrimidin-2-yl)-cycloalkenyl- methylamine scaffold, exhibited excellent CETP inhibitory activity (IC50 = 0.07 μM) in vitro. Furthermore, it showed an acceptable pharmacokinetic profile in S-D rats and efficient HDL-C increase in high-fat fed hamsters.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.