Discovery and Structure-Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists
文献类型：期刊论文
| 作者 | Chen, Zhixiang1,2; Ning, Mengmeng2 ; Zou, Qingan2; Cao, Hua2; Ye, Yangliang2; Leng, Ying2; Shen, Jianhua2
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| 刊名 | CHEMICAL & PHARMACEUTICAL BULLETIN
 |
| 出版日期 | 2016-04 |
| 卷号 | 64期号:4页码:326-339 |
| 关键词 | Takeda G-protein-coupled receptor 5 agonist bioisostere microsomal clearance structure-activity relationship |
| ISSN号 | 0009-2363 |
| DOI | 10.1248/cpb.c15-00905 |
| 文献子类 | Article |
| 英文摘要 | A novel therapy that stimulates endogenous glucagon-like peptide-1 (GLP-1) secretion by Takeda G-protein -coupled receptor 5 (TGR5) agonists might be a superior alternative for the treatment of type 2 diabetes mellitus. A series of 4-phenoxythiazol-5-carboxamides were developed as highly potent TGR5 agonists using a bioisosteric replacement strategy based on the scaffold of 4-phenoxynicotinamides. The structure activity relationship on the bottom phenyl ring and the thiazole ring was extensively studied, and the 2-methylthiazole derivatives 30c and e displayed the best in vitro potency toward human TGR5, with EC50 values of approximately 1nm. While endowed with excellent in vitro potency, the 2-methyl-thiazoles were flawed with high microsomal clearance. |
| WOS关键词 | GLUCAGON-LIKE PEPTIDE-1 ; BILE-ACID RECEPTOR ; GPBAR1 TGR5 ; DERIVATIVES ; DESIGN ; OPTIMIZATION ; ACTIVATION ; SECRETION |
| 资助项目 | Grant from "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 ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000373246300006 |
| 出版者 | PHARMACEUTICAL SOC JAPAN |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276096]  |
| 专题 | 药物发现与设计中心 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 药理学第一研究室 |
| 通讯作者 | Ye, Yangliang; Leng, Ying |
| 作者单位 | 1.Nanchang Univ, Coll Pharm, Nanchang 330006, Peoples R China; 2.Chinese Acad Sci, SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Zhixiang,Ning, Mengmeng,Zou, Qingan,et al. Discovery and Structure-Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists[J]. CHEMICAL & PHARMACEUTICAL BULLETIN,2016,64(4):326-339. |
| APA | Chen, Zhixiang.,Ning, Mengmeng.,Zou, Qingan.,Cao, Hua.,Ye, Yangliang.,...&Shen, Jianhua.(2016).Discovery and Structure-Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists.CHEMICAL & PHARMACEUTICAL BULLETIN,64(4),326-339. |
| MLA | Chen, Zhixiang,et al."Discovery and Structure-Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists".CHEMICAL & PHARMACEUTICAL BULLETIN 64.4(2016):326-339. |
入库方式： OAI收割
来源：上海药物研究所
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