Discovery of novel N,N-3-phenyl-3-benzylaminopropionanilides as potent inhibitors of cholesteryl ester transfer protein in vivo

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• 作者：Honglei Xie ; Yiqun Li ; Changlin Bai ; Ruifeng Wang ; Chunchi Liu ; Chenzhou Hao ; Bin Lin ; Maosheng Cheng ; Dongmei Zhao ; ^{medchemzhao@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CETP inhibitor ; N ; N-3-Phenyl-3-benzylaminopropionanilide derivatives ; Microsomal stability ; Dose-dependent
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：24
• 期：8
• 页码：1811-1818
• 全文大小：809 K

文摘

Epidemiological studies have identified that the risk of cardiovascular events increases due to the decreased levels of high density lipoprotein-cholesterol and the elevated levels of low density lipoprotein-cholesterol. Herein, we report a novel series of N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which were identified as potent cholesteryl ester transfer protein (CETP) inhibitor. The initial lead compound L10 (IC₅₀ 8.06 μM) was found by pharmacophore-based virtual screening (Dong-Mei Zhao et al., Chin. Chem. Lett.2014, 25, 299). After systematic structure variation and biological testing against CETP, two different series were identified as scaffolds for potent CETP inhibitors. One is N,N-3-phenyl-3-benzylaminopropanamide derivatives, which were investigated in our previous paper (Bioorg. Med. Chem.2015, doi: http://dx.doi.org/10.1016/j.bmc.2015.12.010). The most potent compound HL16 in that series has the IC₅₀ of 0.69 μM. The other series is N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which was investigated in current study. Further optimization of the structure–activity relationship (SAR) resulted in H16 (IC₅₀ 0.15 μM), which was discovered as a potent CETP inhibitor in vitro by BODIPY-CE fluorescence assay. In addition, the results of pharmacodynamics studies showed that H16 exhibited both favorable HDL-C enhancement and LDL-C reduction in vivo by hamster. It also has an excellent stability in rat liver microsomal.