Discovery of a low-systemic-exposure DGAT-1 inhibitor with a picolinoylpyrrolidine-2-carboxylic acid moiety

doi:10.1016/j.bmc.2017.07.007

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	Discovery of a low-systemic-exposure DGAT-1 inhibitor with a picolinoylpyrrolidine-2-carboxylic acid moiety
	Yan, Jianwei 1,2; Wang, Gaihong 2; Dang, Xiangyu 2; Guo, Binbin 2; Chen, Wuhong 2; Wang, Ting 2; Zeng, Limin 2; Wang, Heyao2 ; Hu, Youhong2
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	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.
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关键词	ACYLTRANSFERASE 1 DGAT1 ; DIACYLGLYCEROL ACYLTRANSFERASE ; TRIGLYCERIDE SYNTHESIS ; POTENT ; OBESITY ; IDENTIFICATION ; DERIVATIVES ; ANALOGS ; ENZYMES ; TARGET
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000407831300016
内容类型	期刊论文
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.