title: Design, synthesis and biological evaluation of novel cholesteryl ester transfer protein inhibitors bearing a cycloalkene scaffold.
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.
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Chunchi
authors.initials: C
authors.lastname: Liu
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Changqun
authors.initials: C
authors.lastname: Luo
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Hao
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Honglei
authors.initials: H
authors.lastname: Xie
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Shizhen
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Chenzhou
authors.initials: C
authors.lastname: Hao
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: medchemzhao@163.com.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Cheng
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D006224:Cricetinae; D003516:Cycloparaffins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D059305:Diet, High-Fat / Q000009:adverse effects; D015195:Drug Design; D008297:Male; D051381:Rats
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D003516:Cycloparaffins
keywords: CETP inhibitors; Cardiovascular disease; HDL-C; N,N-substituted-cycloalkenyl-methylamine derivatives; Synthesis