基于药效团新型3-(3%2c4-二氯苯基-4-取代苄基)氨基-N-丙酰胺类CETP抑制剂设计、合成及生物活性评价.pdfVIP

基于药效团的新型3-(3,4-二氯苯基-4-取代苄基) 氨基-N-丙酰胺类CETP抑制剂的设计、合成及生物活性评价 * * 赵冬梅 ，郝晨洲，李文艳，熊绪琼，刘春池，程卯生 （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，辽宁 沈阳 110016） 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。 关键词:胆固醇酯转运蛋白；CETP抑制剂；药效团；虚拟筛选，合成 Pharmacophore-based design, synthesis, and biological evaluation of novel 3-((3,4-dichlorophenyl)(4-substituted benzyl)amino)propanamies as cholesteryl ester transfer protein (CETP) inhibitors * 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.) 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: Cho