Design, synthesis and evaluation of 3-phenoxypyrazine-2-carboxamide derivatives as potent TGR5 agonists

Shizhen Zhao; Le Wang; Jie Wang; Chenwei Wang; Shaowei Zheng; Yajie Fu; Yunfu Li; Wei-Dong Chen; Ruifang Hou; Dongbin Yang; Yan-Dong Wang

doi:10.1039/d1ra08867j

Design, synthesis and evaluation of 3-phenoxypyrazine-2-carboxamide derivatives as potent TGR5 agonists

RSC Adv. 2022 Jan 27;12(6):3618-3629. doi: 10.1039/d1ra08867j. eCollection 2022 Jan 24.

Authors

Shizhen Zhao¹, Le Wang¹, Jie Wang¹, Chenwei Wang¹, Shaowei Zheng¹, Yajie Fu¹, Yunfu Li¹, Wei-Dong Chen^{1

2}, Ruifang Hou¹, Dongbin Yang¹, Yan-Dong Wang³

Affiliations

¹ Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, Hebei Key Laboratory of Liver Disease, People's Hospital of Hebei, School of Medicine, Henan University Kaifeng China dr_rfhou@126.com dongbinyang@126.com.
² Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University Hohhot China.
³ State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology Beijing China ydwangbuct2009@163.com.

Abstract

TGR5 is emerging as an important and promising target for the treatment of non-alcoholic steatohepatitis, type 2 diabetes mellitus (T2DM), and obesity. A series of novel 3-phenoxypyrazine-2-carboxamide derivatives were designed, synthesized and evaluated in vitro and in vivo. The most potent compounds 18g and 18k exhibited excellent hTGR5 agonist activity, which was superior to those of the reference drug INT-777. In addition, compound 18k could significantly reduce blood glucose levels in C57 BL/6 mice and stimulate GLP-1 secretion in NCI-H716 cells and C57 BL/6 mice.