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

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• 作者：Hongliang Duan ; Mengmeng Ning ; Xiaoyan Chen ; Qingan Zou ; Liming Zhang ; Ying Feng ; Lina Zhang ; Ying Leng ; Jianhua Shen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10475-10489
• 全文大小：524K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

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鈥?20聽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.