4-Benzofuranyloxynicotinamide derivatives are novel potent and orally available TGR5 agonists
文献类型：期刊论文
| 作者 | Zou, Qingan; Duan, Hongliang; Ning, Mengmeng ; Liu, Jia; Feng, Ying; Zhang, Liming; Zhu, Junjie; Leng, Ying; Shen, Jianhua
|
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2014-07-23 |
| 卷号 | 82页码:1-15 |
| 关键词 | TGR5 4-Benzofuranyloxynicotinamide Gallbladder toxicity Caco-2 permeability |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2014.05.031 |
| 文献子类 | Article |
| 英文摘要 | A series of 4-benzofuranyloxynicotinamide derivatives were identified to be novel, potent, and orally available TGR5 agonists. Among them, compound 9r had the highest potency in vitro (hTGR5 EC50 = 0.28 nM, mTGR5 EC50 = 0.92 nM). Further in vivo studies disclosed that 9r could effectively lower the blood glucose, but meantime caused an increase in the gallbladder volume of mice. Subsequent research toward eliminating the gallbladder toxicity resulted in compound 19 with low permeability. Although the EC50 of mTGR5 of 19 was larger one order than that of 9r, it still had good glucose-lowing activity. Nevertheless, 19 also caused the adverse effects to the gallbladder. The drug levels detection disclosed that the concentration of 19 was only lower than that of 9r in plasma but was higher in bile and gallbladder tissue. This result indicated that low exposure in plasma could not guarantee low exposure in bile and gallbladder tissue, and thus resulting in the gallbladder toxicity of 19. (C) 2014 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | BILE-ACID RECEPTOR ; BILIARY-EXCRETION ; GALLBLADDER ; DRUGS ; PERMEABILITY ; ACTIVATION ; DESIGN ; MUSCLE |
| 资助项目 | National Science and Technology Major Project-Key New Drug Creation and Manufacturing Program, China[2012ZX09103101-049] ; National Nature Science Foundation of China[81202571] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000339039100001 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276979]  |
| 专题 | 药物发现与设计中心 药理学第一研究室 |
| 通讯作者 | Leng, Ying |
| 作者单位 | Chinese Acad Sci, SIMM, Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zou, Qingan,Duan, Hongliang,Ning, Mengmeng,et al. 4-Benzofuranyloxynicotinamide derivatives are novel potent and orally available TGR5 agonists[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2014,82:1-15. |
| APA | Zou, Qingan.,Duan, Hongliang.,Ning, Mengmeng.,Liu, Jia.,Feng, Ying.,...&Shen, Jianhua.(2014).4-Benzofuranyloxynicotinamide derivatives are novel potent and orally available TGR5 agonists.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,82,1-15. |
| MLA | Zou, Qingan,et al."4-Benzofuranyloxynicotinamide derivatives are novel potent and orally available TGR5 agonists".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 82(2014):1-15. |
入库方式： OAI收割
来源：上海药物研究所
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