Discovery of novel potent GPR40 agonists containing imidazo[1, 2-a]pyridine core as antidiabetic agents. Issue 13 (1st July 2020)

• Record Type: Journal Article
• Authors: Ye, Zhiwen; Liu, Chunxia; Zou, Feng; Cai, Yan; Chen, Bin; Zou, Yuxing; Mo, Jiaxian; Han, Ting; Huang, Wenlong; Qiu, Qianqian; Qian, Hai
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 13(2020)
• Publication Date: 2020-07-01
• Subjects: Type 2 diabetes mellitus -- GPR40 agonists -- Phenylpropanoic acid -- Hepatotoxicity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115574
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.