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

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.