Design, synthesis and biological evaluation of N,N-3-phenyl-3-benzylaminopropanamide derivatives as novel cholesteryl ester transfer protein inhibitor

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• 作者：Dongmei Zhao^a ; ^{medchemzhao@163.com" class="auth_mail" title="E-mail the corresponding author} ; Honglei Xie^a ; Changlin Bai^a ; Chunchi Liu^a ; Chenzhou Hao^a ; Shizhen Zhao^a ; Hongli Yuan^a ; Changqun Luo^a ; Jian Wang^a ; Bin Lin^a ; Jiang Zheng^a ; ^b ; Maosheng Cheng^a
• 关键词：CETP inhibitor ; N ; N-3-phenyl-3-benzylaminopropanamides derivatives ; Molecular docking
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：24
• 期：8
• 页码：1589-1597
• 全文大小：3364 K

文摘

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.