吡咯烷类活化Ⅸ因子抑制剂的设计、合成及活性研究  

Design, synthesis and activity evaluation of pyrrolidine compounds as FⅨa inhibitors

作　　者：徐亭亭 石慧 李灵君[2] 刘磊 张宝钰 黄长江[2] 王平保[2] 袁静[2] XU Ting-ting;SHI Hui;LI Ling-jun;LIU Lei;ZHANG Bao-yu;HUANG Chang-jiang;WANG Ping-bao;YUAN Jing(School of Pharmacy,Tianjin Medical University,Tianjin 300041,China;Tianjin Key Laboratory of Molecular Design and Drug Discovery,Tianjin Institute of Pharmaceutical Research,Tianjin 300457,China)

机构地区：[1]天津医科大学药学院,天津300041 [2]天津药物研究院,天津市新药设计与发现重点实验室,天津300457

出　　处：《中国药物化学杂志》2021年第4期249-260,共12页Chinese Journal of Medicinal Chemistry

基　　金：天津市科技计划项目(19YFZCSY00620)。

摘　　要：目的活化Ⅸ因子(FⅨa)是针对静脉血栓疾病研究中十分具有吸引力的靶点。为了寻找安全、有效、用药便捷的新型口服抗凝药物,针对FⅨa靶点设计了18个吡咯烷类化合物。方法经过烷基化反应、酰基化反应、迈克尔加成反应、缩合反应、水解反应等对目标化合物进行化学合成,所获得的化合物经过^(1)H-NMR、MS等手段进行了结构确证;采用离体酶抑制法测定化合物的FⅨa抑制活性。结果发现了苗头化合物A_(i)显示出FⅨa抑制活性。结论通过分子对接模拟化合物A_(i)和阳性对照CFM-184与靶点的作用模式,揭示了二者的差异,为后续FⅨa抑制剂的研发提供思路。Activated factor Ⅸ(FⅨa) is an attractive target in the study of venous thromboembolism.In order to find novel oral anticoagulants, which are safe, effective and convenient administration, 18 pyrrolidine compounds were designed as FⅨa inhibitors.The target compounds were synthesized via alkylation, acylation, Michael addition, condensation and hydrolysis reaction.The structures of the obtained compounds were confirmed by ^(1)H-NMR and MS.FⅨa inhibitory activity of these compounds was evaluated by enzyme inhibition method in vitro,and compound A_(i) showed inhibitory activity.By simulating the action mode with the target based on molecular docking, the differences between compound A_(i) and positive control CFM-184 have been revealed.

关 键 词：静脉血栓 活化Ⅸ因子抑制剂 构效关系 分子对接 

分 类 号：R914[医药卫生—药物化学]