【作者】 赵冬梅； 郝晨洲； 李文艳； 熊绪琼； 刘春池； 程卯生；

【Author】 ZHAO Dongmei,HAO Chenzhou,LI Wenyan,XIONG Xuqiong,LIU Chunchi,CHENG Maosheng(Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, China.)

【机构】 沈阳药科大学基于靶点的药物设计与研究教育部重点实验室；

【摘要】 目的发现结构新颖、活性优良的小分子CETP抑制剂,为开发新一代防治动脉粥样硬化的调脂药物奠定基础。方法利用已报道的56个CETP抑制剂构建药效团模型,虚拟筛选ZINC/big-n-greasy数据库发现先导化合物,在此基础上改造、合成得到一系列3-(3,4-二氯苯基-4-取代苄基)氨基-N-丙酰胺类衍生物。采用同位素标记法测试所合成化合物的CETP抑制活性。结果合成了8个新的目标化合物,均具有一定的CETP抑制活性,其中化合物4j活性最强,与阳性对照相当。结论该类化合物具有进一步的研究价值。更多还原

【Abstract】 OBJECTIVE To pave a road towards discovering some novel, potent small-molecule CETP inhibitors with significant promise for the treatment of atherosclerosis. METHODS 56 CETP inhibitors were utilized to construct the pharmacophore models and pharmacophore-based virtual screening of the ZINC/big-n-greasy database, leading to the identification of compound H10 as a potential CETP inhibitor in vitro.A series of 3-((3,4-dichlorophenyl)(4-substituted benzyl)amino) propanamides were designed, synthesized, and evaluated by radioisotope-based assay. RESULTS Compound 4j was found to have the best activity, resulting in 85.0% inhibition of CETP at 10 μM. CONCLUSION These compounds were worth to further development. KEY WARDS: Cholesteryl ester transfer protein, CETP inhibitors, Pharmacophore, Virtual screening, Synthesis更多还原