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

• DOI: 10.1016/j.ejmech.2016.07.065
• Publication Date: 2016-07-28T21:23:41Z
• Authors: Chunchi Liu; Changqun Luo; Lijuan Hao; Qiong Wu; Honglei Xie; Shizhen Zhao; Chenzhou Hao; Dongmei Zhao; Maosheng Cheng
• Keywords: Male; 0301 basic medicine; 03 medical and health sciences; Cricetinae; Drug Design; Animals; Cycloparaffins; Chemistry Techniques, Synthetic; Diet, High-Fat; Cholesterol Ester Transfer Proteins; Rats; 3. Good health

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.