Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists

被引：75

作者：

Duan, Hongliang ^{[1
]}

Ning, Mengmeng ^{[1
]}

Chen, Xiaoyan ^{[1
]}

Zou, Qingan ^{[1
]}

Zhang, Liming ^{[1
]}

Feng, Ying ^{[1
]}

Zhang, Lina ^{[1
]}

Leng, Ying ^{[1
]}

Shen, Jianhua ^{[1
]}

机构：

[1] Chinese Acad Sci, State Key Lab Drug Res, SIMM, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 23期

关键词：

BILE-ACID RECEPTOR; METABOLITE; SECRETION;

D O I：

10.1021/jm301071h

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists are reported. Several 4-phenoxynicotinamide derivatives were found to activate human and mouse TGR5 (hTGR5 and mTGR5) with EC50 values in the low nanomolar range. Compound 23g, with an EC50 value of 0.72 nM on hTGR5 and an EC50 value of 6.2 nM on mTGR5, was selected for further in vivo efficacy studies. This compound exhibited a significant dose-dependent glucagon-like peptide-1 (GLP-1) secretion effect. A single oral dose of 23g (50 mg/kg) significantly reduced blood glucose levels in db/db mice and caused a 49% reduction in the area under the blood glucose curve (AUC)(0-120) (min) following an oral glucose tolerance test (OGTT) in imprinting control region (ICR) mice. However, 23g stimulated gallbladder filling, which might result in side effects to the gallbladder.

引用

页码：10475 / 10489

页数：15

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