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

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

Shizhen Zhao  1 , Le Wang  1 , Jie Wang  1 , Chenwei Wang  1 , Shaowei Zheng  1 , Yajie Fu  1 , Yunfu Li  1 , Wei-Dong Chen  1   2 , Ruifang Hou  1 , Dongbin Yang  1 , Yan-Dong Wang  3
Affiliations

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

Shizhen Zhao et al. RSC Adv. .

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.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Structures of some known TGR5 agonists.
Scheme 1
Scheme 1. Synthesis of intermediates 1a–f. Reagents and conditions: (a) cyclopropylamine, r.t.; (b) methyl oxalyl chloride, triethylamine, CH2Cl2, r.t.; (c) Pd/C, H2, MeOH, r.t.; (d) triphenylphosphine, DMF, 135 °C; (e) BH3–THF, THF, r.t.
Scheme 2
Scheme 2. Synthesis of intermediates 13–16. Reagents and conditions:(a) NaH, DMF, 4-chlorobenzyl bromide; (b) K2CO3, substituted phenol.
Scheme 3
Scheme 3. General synthesis of the target compounds 18a–u. Reagents and conditions: (a) NaOH, MeOH/H2O, r.t.; (b) HATU, DIEA, DMF, 60 °C.
Fig. 2
Fig. 2. Oral glucose tolerance test (OGTT) of compound 18k in male C57BL/6 mice. (A) Blood glucose concentration; (B) blood glucose AUC0–120 min. Compounds 18k (50 mg kg−1 in corn oil) or corn oil (control) was orally administered at −60 min of OGTT followed by oral glucose challenge at 4.0 g kg−1 at 0 min. n = 7–8 animals per group. *P < 0.05 vs. control. Error bar indicates SEM (standard error of the mean).
Fig. 3
Fig. 3. GLP-1 secretion study of compound 18k at 4 μM in NCI-H716 cells and 50 mg kg−1 in C57 BL/6 mice. *P < 0.05; ***P < 0.001 versus control; error bar indicates SEM.
Fig. 4
Fig. 4. The binding mode of compounds 18k in the active site of TGR5 (PDB ID 7CFM).
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