Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists
文献类型：期刊论文
| 作者 | Duan, Hongliang; Ning, Mengmeng ; Chen, Xiaoyan; Zou, Qingan; Zhang, Liming; Feng, Ying; Zhang, Lina; Leng, Ying; Shen, Jianhua
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2012-12-13 |
| 卷号 | 55期号:23页码:10475-10489 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/jm301071h |
| 文献子类 | Article |
| 英文摘要 | 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. |
| WOS关键词 | BILE-ACID RECEPTOR ; TYPE-2 DIABETES-MELLITUS ; METABOLITE ; SECRETION ; MICE |
| 资助项目 | National Science and Technology Major Project - Key New Drug Creation and Manufacturing Program, China[2012ZX09103101-049] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000312227300014 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277844]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物发现与设计中心 |
| 通讯作者 | Leng, Ying |
| 作者单位 | Chinese Acad Sci, State Key Lab Drug Res, SIMM, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Duan, Hongliang,Ning, Mengmeng,Chen, Xiaoyan,et al. Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists[J]. JOURNAL OF MEDICINAL CHEMISTRY,2012,55(23):10475-10489. |
| APA | Duan, Hongliang.,Ning, Mengmeng.,Chen, Xiaoyan.,Zou, Qingan.,Zhang, Liming.,...&Shen, Jianhua.(2012).Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists.JOURNAL OF MEDICINAL CHEMISTRY,55(23),10475-10489. |
| MLA | Duan, Hongliang,et al."Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists".JOURNAL OF MEDICINAL CHEMISTRY 55.23(2012):10475-10489. |
入库方式： OAI收割
来源：上海药物研究所
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