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

Zhiwen Ye; Chunxia Liu; Feng Zou; Yan Cai; Bin Chen; Yuxing Zou; Jiaxian Mo; Ting Han; Wenlong Huang; Qianqian Qiu; Hai Qian

doi:10.1016/j.bmc.2020.115574

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. Epub 2020 Jun 2.

Authors

Zhiwen Ye¹, Chunxia Liu¹, Feng Zou¹, Yan Cai¹, Bin Chen¹, Yuxing Zou¹, Jiaxian Mo¹, Ting Han¹, Wenlong Huang², Qianqian Qiu³, Hai Qian⁴

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: qianqianqiu_cpu@126.com.
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: qianhai24@163.com.

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, t_1/2 = 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzofurans / pharmacology
Blood Glucose / drug effects
Diabetes Mellitus, Experimental / drug therapy
Diabetes Mellitus, Type 2 / drug therapy*
Drug Evaluation, Preclinical
Glucose Tolerance Test
Humans
Hypoglycemic Agents / adverse effects
Hypoglycemic Agents / chemical synthesis*
Hypoglycemic Agents / pharmacokinetics
Male
Mice
Mice, Inbred C57BL
Phenylpropionates / chemistry
Pyridines / adverse effects
Pyridines / chemical synthesis*
Pyridines / pharmacokinetics
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled / agonists*
Sulfones / pharmacology

Substances

Benzofurans
Blood Glucose
Hypoglycemic Agents
Phenylpropionates
Pyridines
Receptors, G-Protein-Coupled
Sulfones
TAK-875