Hanmi Research Center, Hanmi Pharm. Co., Ltd., Hwaseong-si, 18469, Republic of Korea; College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, 06974, Republic of Korea.
College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, 06974, Republic of Korea.
Eur J Med Chem. 2023 Oct 5;258:115584. doi: 10.1016/j.ejmech.2023.115584. Epub 2023 Jun 19.
G-protein-coupled receptor 119 (GPR119) has great potential as a therapeutic target for the treatment of type II diabetes. Novel thieno[3,2-d]pyrimidine derivatives were discovered as GPR119 agonists through a bioisosteric replacement strategy. The sulfonylphenyl thieno[3,2-d] pyrimidine scaffold was introduced, and its derivatives exhibited potent agonistic activity for GPR119 in cell-based assays. The representative derivative 43 displayed excellent pharmacokinetic profiles in rodents and significantly improved glucose tolerance in vivo. In OGTT study, compound 43 reduced significantly blood glucose levels in both mice and rats.
G 蛋白偶联受体 119（GPR119）作为治疗 II 型糖尿病的治疗靶点具有巨大的潜力。通过生物等排替换策略，发现新型噻吩并[3,2-d]嘧啶衍生物是 GPR119 的激动剂。引入磺酰基苯基噻吩并[3,2-d]嘧啶骨架，其衍生物在基于细胞的测定中对 GPR119 表现出很强的激动活性。代表性衍生物 43 在啮齿动物中表现出优异的药代动力学特性，并在体内显著改善葡萄糖耐量。在 OGTT 研究中，化合物 43 可显著降低小鼠和大鼠的血糖水平。
