Discovery of novel potent GPR40 agonists containing imidazo[1,2-a]pyridine core as antidiabetic agents

  • Bioorg Med Chem. 2020 Jul 1;28(13):115574. doi: 10.1016/j.bmc.2020.115574.
Zhiwen Ye  1 ,  Chunxia Liu  1 ,  Feng Zou  1 ,  Yan Cai  1 ,  Bin Chen  1 ,  Yuxing Zou  1 ,  Jiaxian Mo  1 ,  Ting Han  1 ,  Wenlong Huang  2 ,  Qianqian Qiu  3 ,  Hai Qian  4
Affiliations
  • 1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 2. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 3. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: [email protected].
  • 4. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: [email protected].
PMID: 32546302 DOI: 10.1016/j.bmc.2020.115574
Abstract

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. Compound I-14 was 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 of I-14 were observed (CL = 27.26 ml/h/kg, t1/2 = 5.93 h). The results indicate that I-14 could serve as a possible candidate to treat diabetes.

Keywords
GPR40 agonists; Hepatotoxicity; Phenylpropanoic acid; Type 2 diabetes mellitus.
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