以宿主细胞蛋白为靶点的新型HCV抑制剂的合成与构效关系研究

项目名称： 以宿主细胞蛋白为靶点的新型HCV抑制剂的合成与构效关系研究

项目编号： No.81202414

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 李艳萍

作者单位： 中国医学科学院医药生物技术研究所

项目金额： 23万元

中文摘要： 目前临床上HCV治疗药物匮乏，现有药物存在不良反应多，易耐药的缺陷。以宿主细胞蛋白为靶点的抗病毒药物因为具有作用机制新颖和不易诱发耐药的优势，在近年来受到越来越多的关注。本课题在前期HCV抑制剂研究中发现了以宿主细胞蛋白APOBEC3G为靶点的小分子先导物IMB-26，并进行了初步的构效关系研究。前期研究发现了多个抗病毒活性强，治疗指数高的新化合物，但同时也发现了这类化合物结构稳定性差，容易断裂失活,产生毒性的缺陷。因此，本研究将以增加化学结构稳定性，降低毒性为主要目的，设计合成三类(α-苯氨基苯乙酮、二氢苯并恶嗪和异二氢吲哚酮)有利于改善稳定性的新骨架结构，并进行构效关系和体外代谢稳定性研究。通过本研究，希望衍生出HCV抑制剂的新结构类型，并找到代谢相对稳定的新型先导化合物。

中文关键词： 丙型肝炎病毒；抑制剂；构效关系；APOBEC3G；设计合成

英文摘要： Safe HCV therapy drug is less available in clinic nowadays. Host-targeting antiviral agents emerge recently and attracted more and more attention owing to their novel action mechanism and high resistance barrier. Small molecule compound IMB-26 targeting host cellular factor APOBEC3G was found to be active in vitro at low micromole level against HCV in our previous study. The initial optimization and structure-activity relationship study of IMB-26 produced several potential compounds against HCV with much higher therapy index than IMB-26. However, these compounds were also found to be unstable. The linkage between two benzene rings was prone to break down which resulted in loss of antiviral activity and produced toxic metabolites. With the aim of finding more stable anti-HCV compounds, this study was planned to design and synthesis three novel chemical structure types(α-phenylamino phenyl ethanone, dihydrobenzoxazine, isoindolinone)based on IMB-26 for further SAR study. The synthesized target compounds would be tested of anti-HCV activity and stability in vitro. The study is expected to afford stable structure skeleton for HCV inhibitor, and find metabolism endurable,less toxic and novel anti-HCV lead compound.

英文关键词： hepatitis C virus；inhibitors；SAR；APOBEC3G；design and synthesis