Issue 6, 2022, Issue in Progress
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RSC Advances

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

Shizhen Zhao, ORCID logo ‡a   Le Wang,‡a   Jie Wang,a   Chenwei Wang,a   Shaowei Zheng,a   Yajie Fu,a   Yunfu Li,a   Wei-Dong Chen, ORCID logo ab   Ruifang Hou,*a   Dongbin Yang*a  and  Yan-Dong Wang*c  

* Corresponding authors

a 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
E-mail: dr_rfhou@126.com, dongbinyang@126.com

b Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China

c State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
E-mail: 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.

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

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Article information

DOI
https://doi.org/10.1039/D1RA08867J
Article type
Paper
Submitted
06 Dec 2021
Accepted
15 Jan 2022
First published
27 Jan 2022
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2022,12, 3618-3629

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

S. Zhao, L. Wang, J. Wang, C. Wang, S. Zheng, Y. Fu, Y. Li, W. Chen, R. Hou, D. Yang and Y. Wang, RSC Adv., 2022, 12, 3618 DOI: 10.1039/D1RA08867J

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