Discovery of a low-systemic-exposure DGAT-1 inhibitor with a picolinoylpyrrolidine-2-carboxylic acid moiety
文献类型：期刊论文
| 作者 | Yan, Jianwei1,2; Wang, Gaihong2; Dang, Xiangyu2; Guo, Binbin2; Chen, Wuhong2; Wang, Ting2; Zeng, Limin2; Wang, Heyao2 ; Hu, Youhong2
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
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| 出版日期 | 2017-09-01 |
| 卷号 | 25期号:17页码:4701-4714 |
| 关键词 | DGAT-1 Inhibitor Triglyceride Hyperlipidemia |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2017.07.007 |
| 文献子类 | Article |
| 英文摘要 | A series of diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors with a picolinoylpyrrolidine2-carboxylic acid moiety were designed and synthesized. Of these compounds, compound 22 exhibited excellent DGAT-1-inhibitory activity (hDGAT-1 enzyme assay, 50% inhibitory concentration [IC50] = 3.5 +/- 0.9 nM) and effectively reduced the intracellular triglyceride contents in 3T3-L1, HepG2 and Caco-2 cells. A preliminary study of the plasma and tissue distributions of compound 22 in mice revealed low plasma exposure and high concentrations in different segments of the intestine and liver, which may facilitate targeting DGAT-1. Furthermore, in an acute lipid challenge test, compound 22 showed a dose-dependent inhibitory effect on high-serum triglycerides in C57/KSJ mice induced by olive oil (1, 3, and 10 mg/kg, i.g.). (C) 2017 Elsevier Ltd. All rights reserved. |
| WOS关键词 | ACYLTRANSFERASE 1 DGAT1 ; DIACYLGLYCEROL ACYLTRANSFERASE ; TRIGLYCERIDE SYNTHESIS ; POTENT ; OBESITY ; IDENTIFICATION ; DERIVATIVES ; ANALOGS ; ENZYMES ; TARGET |
| 资助项目 | National Natural Science Foundation of China[81225022] ; National Natural Science Foundation of China[81503124] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120162025] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000407831300016 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272513]  |
| 专题 | 药理学第三研究室 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 药物化学研究室 |
| 通讯作者 | Wang, Heyao; Hu, Youhong |
| 作者单位 | 1.Xinxiang Med Univ, Sch Pharm, 601 Jisui Ave, Xinxiang 453003, Henan, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 ZuChongZhi Rd, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Yan, Jianwei,Wang, Gaihong,Dang, Xiangyu,et al. Discovery of a low-systemic-exposure DGAT-1 inhibitor with a picolinoylpyrrolidine-2-carboxylic acid moiety[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2017,25(17):4701-4714. |
| APA | Yan, Jianwei.,Wang, Gaihong.,Dang, Xiangyu.,Guo, Binbin.,Chen, Wuhong.,...&Hu, Youhong.(2017).Discovery of a low-systemic-exposure DGAT-1 inhibitor with a picolinoylpyrrolidine-2-carboxylic acid moiety.BIOORGANIC & MEDICINAL CHEMISTRY,25(17),4701-4714. |
| MLA | Yan, Jianwei,et al."Discovery of a low-systemic-exposure DGAT-1 inhibitor with a picolinoylpyrrolidine-2-carboxylic acid moiety".BIOORGANIC & MEDICINAL CHEMISTRY 25.17(2017):4701-4714. |
入库方式： OAI收割
来源：上海药物研究所
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