Discovery of novel potent GPR40 agonists containing imidazo 1,2-a pyridine core as antidiabetic agents
Discovery of novel potent GPR40 agonists containing imidazo 1,2-a pyridine core as antidiabetic agents
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发现含有咪唑并 1,2-a 吡啶核心的新型强效 GPR40 激动剂作为抗糖尿病药物
DOI：
10.1016/j.bmc.2020.115574
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发表时间：
2020
影响因子：
3.5
通讯作者：
Hai Qian
中科院分区：
文献类型：
--
作者：
Zhiwen Ye;Chunxia Liu;Feng Zou;Yan Cai;Bin Chen;Yuxing Zou;Jiaxian Mo;Ting Han;Wenlong Huang;Qianqian Qiu;Hai Qian
游离脂肪酸受体1（FFA 1或GPR 40）作为治疗2型糖尿病的靶点已研究多年。为了提高药效和降低肝毒性，合成了一系列含咪唑并[1，2-a]吡啶骨架的新型化合物作为GPR 40激动剂。化合物I-14被鉴定为有效的激动剂，如在正常和糖尿病小鼠中的血糖的显著下降所示。与TAK-875相比，无肝毒性风险。此外，观察到I-14的良好药代动力学（PK）特性（CL = 27.26 ml/h/kg，t1/2= 5.93 h）。结果表明，I-14可作为治疗糖尿病的候选药物。
Free fatty acid receptor 1 (FFA1 or GPR40) has been studied for many years as a target for the treatment of type 2 diabetes mellitus. In order to increase potency and reduce hepatotoxicity, a series of novel compounds containing imidazo[1,2-a]pyridine scaffold as GPR40 agonist were synthesized. CompoundI-14was identified as an effective agonist as shown by the conspicuous drop in blood glucose in normal and diabetic mice. It had no risk of hepatotoxicity compared with TAK-875. Moreover, good pharmacokinetic (PK) properties ofI-14were observed (CL = 27.26 ml/h/kg, t1/2= 5.93 h). The results indicate thatI-14could serve as a possible candidate to treat diabetes.