Design, Synthesis, and Structure-Activity Relationships of 3,4,5-Trisubstituted 4,5-Dihydro-1,2,4-oxadiazoles as TGR5 Agonists
文献类型：期刊论文
| 作者 | Zhu, Junjie2; Ye, Yangliang2 ; Ning, Mengmeng2; Mandi, Attila1; Feng, Ying2; Zou, Qingan2; Kurtan, Tibor1; Leng, Ying2; Shen, Jianhua2
|
| 刊名 | CHEMMEDCHEM
 |
| 出版日期 | 2013-07 |
| 卷号 | 8期号:7页码:1210-1223 |
| 关键词 | 4 5-dihydro-1 2 4-oxadiazoles cycloaddition metabolic disorders structure-activity relationships TGR5 |
| ISSN号 | 1860-7179 |
| DOI | 10.1002/cmdc.201300144 |
| 文献子类 | Article |
| 英文摘要 | Given its role in the mediation of energy and glucose homeostasis, the G-protein-coupled bile acid receptor1 (TGR5) is considered a potential target for the treatment of type2 diabetes mellitus and other metabolic disorders. By thorough analysis of diverse structures of published TGR5 agonists, a hypothetical ligand-based pharmacophore model was built, and a new class of potent TGR5 agonists, based on the novel 3,4,5-trisubstituted 4,5-dihydro-1,2,4-oxadiazole core, was discovered by rational design. Three distinct synthetic methods for constructing 4,5-dihydro-1,2,4-oxadiazoles and extensive structure-activity relationship studies are reported herein. Compound (R)-54n, the structure of which was determined by single-crystal X-ray diffraction and quantum chemical solid-state TDDFT-ECD calculations, showed the best potency, with an EC50 value of 1.4nM toward hTGR5. Its favorable properties invitro warrant further investigation. |
| WOS关键词 | TYPE-2 DIABETES-MELLITUS ; BILE-ACID DERIVATIVES ; RECEPTOR ANTAGONISTS ; POTENT AGONISTS ; NITRILE OXIDES ; SOLID-STATE ; DRUG DESIGN ; PROTEIN ; CYCLOADDITION ; INHIBITOR |
| 资助项目 | National Science and Technology Major Project-Key New Drug Creation and Manufacturing Program, China[2012ZX09103101-049] ; Hungarian National Research Foundation[OTKA K105871] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000320928400015 |
| 出版者 | WILEY-V C H VERLAG GMBH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277564]  |
| 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 | Leng, Ying |
| 作者单位 | 1.Univ Debrecen, Dept Organ Chem, H-4010 Debrecen, Hungary 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhu, Junjie,Ye, Yangliang,Ning, Mengmeng,et al. Design, Synthesis, and Structure-Activity Relationships of 3,4,5-Trisubstituted 4,5-Dihydro-1,2,4-oxadiazoles as TGR5 Agonists[J]. CHEMMEDCHEM,2013,8(7):1210-1223. |
| APA | Zhu, Junjie.,Ye, Yangliang.,Ning, Mengmeng.,Mandi, Attila.,Feng, Ying.,...&Shen, Jianhua.(2013).Design, Synthesis, and Structure-Activity Relationships of 3,4,5-Trisubstituted 4,5-Dihydro-1,2,4-oxadiazoles as TGR5 Agonists.CHEMMEDCHEM,8(7),1210-1223. |
| MLA | Zhu, Junjie,et al."Design, Synthesis, and Structure-Activity Relationships of 3,4,5-Trisubstituted 4,5-Dihydro-1,2,4-oxadiazoles as TGR5 Agonists".CHEMMEDCHEM 8.7(2013):1210-1223. |
入库方式： OAI收割
来源：上海药物研究所
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