| Pharmacophore-based design,synthesis, and biological evaluation of novel 3-（（3,4-dichlorophenyl）（4-substituted benzyl）amino） propanamides as cholesteryl ester transfer protein （CETP） inhibitors |
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| 作者姓名： | Dong-Mei Zhao Wen-Yan Li Yu-Fang Shi Xu-Qiong Xiong Shuai Song Chen-Zhou Ha Mao-Sheng Cheng Jing-Kang Shen |
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| 作者单位： | [1]Key Laboratory of Structure-Based Drugs Design ＆ Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China [2]Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203, China |
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| 基金项目： | The authors thank Yi-Ping Wang of the Shanghai Institute of Materia Medica, Chinese Academy of Science for the activity assays. |
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| 摘 要： | Cholesteryl ester transfer protein （CETP） is a plasma glycoprotein that plays an important role in decreasing high-density lipoprotein cholesterol （HDL-C） levels and increasing low-density lipoprotein cholesterol （LDL-C） levels. Inhibition of CETP may be a new therapy for treating atherosclerosis. Herein, we report the development of a ligand-based pharmacophore model and pharmacophore-based virtual screening of the ZINC/big-n-greasy database, leading to the identification of compound H-10 as a potential CETP inhibitor in vitro. Based on H-10, a series of 3-（（3,4-dichlorophenyl）（4-substituted benzyl）amino） propanamides were designed, synthesized, and evaluated against CETP. Compound 41 was found to have the best activity, resulting in 85.0% inhibition of CETP at l0 μmol/L.
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| 关 键 词： | 药效团模型 CETP 生物学评价 二氯苯基 胆固醇酯 糖蛋白 抑制剂 设计 |
| 收稿时间： | 2013-06-14 |
| 修稿时间： | 2013-10-23 |
Pharmacophore-based design,synthesis, and biological evaluation of novel 3-((3, 4-dichlorophenyl)(4-substituted benzyl)amino) propanamides as cholesteryl ester transfer protein (CETP) inhibitors |
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| Dong-Mei Zhao,Wen-Yan Li,Yu-Fang Shi,Xu-Qiong Xiong,Shuai Song,Chen-Zhou Ha,Mao-Sheng Cheng,Jing-Kang Shen.Pharmacophore-based design,synthesis, and biological evaluation of novel 3-((3, 4-dichlorophenyl)(4-substituted benzyl)amino) propanamides as cholesteryl ester transfer protein (CETP) inhibitors[J].Chinese Chemical Letters,2014,25(2):299-304. |
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| Authors: | Dong-Mei Zhao Wen-Yan Li Yu-Fang Shi Xu-Qiong Xiong Shuai Song Chen-Zhou Hao Mao-Sheng Cheng Jing-Kang Shen |
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| Institution: | a Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China;
b Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203, China |
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| Abstract: | Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that plays an important role in decreasing high-density lipoprotein cholesterol (HDL-C) levels and increasing low-density lipoprotein cholesterol (LDL-C) levels. Inhibition of CETP may be a new therapy for treating atherosclerosis. Herein, we report the development of a ligand-based pharmacophore model and pharmacophore-based virtual screening of the ZINC/big-n-greasy database, leading to the identification of compound H-10 as a potential CETP inhibitor in vitro. Based on H-10, a series of 3-((3,4-dichlorophenyl)(4-substituted benzyl)amino) propanamides were designed, synthesized, and evaluated against CETP. Compound 4l was found to have the best activity, resulting in 85.0% inhibition of CETP at 10 μmol/L. |
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| Keywords: | Cholesteryl ester transfer protein CETP inhibitors Pharmacophore Virtual screening Synthesis |
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