title: Design, synthesis and biological evaluation of N,N-3-phenyl-3-benzylaminopropanamide derivatives as novel cholesteryl ester transfer protein inhibitor.
abstract: A series of N,N-3-phenyl-3-benzylaminopropanamide derivatives were identified as novel CETP (cholesteryl ester transfer protein) inhibitors. In our previous study, lead compound L10 was discovered by pharmacophore-based virtual screening (Dong-Mei Zhao et al., 2014). Based on L10 (IC50 8.06 μM), compound HL6 (IC50 10.7 μM) was discovered following systematic structure variation and biological tests. Further optimization of the structure-activity relationship (SAR) resulted in N,N-3-phenyl-3-benzylaminopro panamides derivatives as novel CETP inhibitors. They were synthesized and evaluated against CETP by BODIPY-CE fluorescence assay. Among them, HL16 (IC50 0.69 μM) was a highly potent CETP inhibitor in vitro. In addition, HL16 exhibited favorable HDL-C enhancement and LDL-C reduction in vivo by hamster. The molecular docking of HL16 into the CETP was performed. The binding mode demonstrated that HL16 occupied the CETP binding site and formed interactions with the key amino acid residues.
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, 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, 103 Wenhua Road, Shenhe District, 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, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Bai
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, 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, 103 Wenhua Road, Shenhe District, 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, 103 Wenhua Road, Shenhe District, 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, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, 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, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lin
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China; Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98101, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Cheng
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011407:Propane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001596:Benzylamines; D053480:Cholesterol Ester Transfer Proteins; C000612710:N,N-3-phenyl-3-benzylaminopropanamide; D011407:Propane
keywords: CETP inhibitor; Molecular docking; N,N-3-phenyl-3-benzylaminopropanamides derivatives