Structural optimization and bioactivity of a novel acrylic GPR40 agonist
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 EC50 1.68 μmol·L-1 and 4.9 μmol·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.
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