新型丙烯酸类GPR40激动剂的结构优化及其生物活性研究  

Structural optimization and bioactivity of a novel acrylic GPR40 agonist

作　　者：郭凯蕾 魏朝 张东旭 张鑫磊 李琦 孙定康 梁佳龙 马丽莎 林佳艳 何金穗 刁春妍 王斌[1] 刘雪英 GUO Kai-lei;WEI Zhao;ZHANG Dong-xu;ZHANG Xin-lei;LI Qi;SUN Ding-kang;LIANG Jia-long;MA Li-sha;LIN Jia-yan;HE Jin-sui;DIAO Chun-yan;WANG Bin;LIU Xue-ying(Department of Pharmacy,Shaanxi University of Traditional Chinese Medicine,Xianyang Shaanxi 712046;Department of Medicinal Chemsitry,School of Pharmacy,Air Force Medical University,Xi’an 710032;College of Life Sciences,Henan University,Kaifeng Henan 475004;The 946th Hospital of the People’s Liberation Army Ground Force,Yining Xinjiang 835000)

机构地区：[1]陕西中医药大学药学院,陕西咸阳712046 [2]空军军医大学药学系药物化学与药物分析教研室,西安710032 [3]河南大学生命科学学院,河南开封475004 [4]中国人民解放军陆军第九四六医院医疗保障中心,新疆伊宁835000

出　　处：《中南药学》2024年第6期1449-1455,共7页Central South Pharmacy

基　　金：陕西省2021年创新能力支持计划(No.2021GCZX-07号);陕西省秦创原“科学家+工程师”队伍建设(No.2023KXJ-080号)。

摘　　要：目的 以HMT-1为先导化合物,构建新型丙烯酸类抗2型糖尿病药物,并进行构效关系分析。方法 采用基团替换及同系物原则对HMT-1进行结构衍生化设计合成。采用分子对接考察衍生物与GPR40的结合作用模式。通过GPR40激动活性实验评估目标化合物的生物活性。结果 共设计合成了6个丙烯酸类新型GPR40激动剂,体外活性实验发现均具有一定的GPR40激动活性,其中HMT-5和HMT-14的激动活性与HMT-1及阳性药物TAK-875接近。其EC_(50)分别为1.68 μmol·L^(-1)和4.9 μmol·L^(-1)。结论 构效关系分析发现,尾部苯环为对位取代,并在尾部增加氢键供体及连接链为芳香酰胺时可提高活性,可为开发更高效的抗2型糖尿病药物奠定基础。Objective To develop novel anti-type 2 diabetes drugs based on HMT-1,and to determine its structure-activity relationship.Methods The HMT-1 structural derivatives were synthesized by the principles of group position substitution and homology,followed by investigation of their binding mode with GPR40 through molecular docking.Results Six novel acrylic GPR40 agonists were designed and synthesized,and cell experiments demonstrated certain GPR40 agonistic activity.Notably,HMT-5 and HMT-14 exhibited comparable agonistic activity to HMT-1 and the positive control drug TAK-875,with EC501.68μmol·L^(-1) and 4.9μmol·L^(-1),respectively.Conclusion The study of structure-activity relationship has demonstrated that the presence of a para-substituted benzene ring with a hydrogen bond donor as the substituent,coupled with an aromatic amide linker,may effectively enhance GPR40 agonist activity.This research provides a foundation for the development of potential therapeutics for type 2 diabetes.

关 键 词：GPR40 糖尿病 结构优化 丙烯酸 

分 类 号：R14[医药卫生—公共卫生与预防医学] TQ463[化学工程—制药化工]