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Synthesis and biological evaluation of novel potent FFA1 agonists containing 2,3-dihydrobenzo[b][1,4]dioxine

文献类型：期刊论文

作者Kong, Deyu2,3; Guo, Shimeng4; Yang, Yushe3; Guo, Bin3; Xie, Xin4; Hu, Wenhao1,2
刊名BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
出版日期2019-03-15
卷号29期号:6页码:848-852
关键词FFA1 agonist 2,3-Dihydrobenzo[b][1,4]dioxine Insulin secretion Type 2 diabetes mellitus
ISSN号0960-894X
DOI10.1016/j.bmcl.2019.01.014
通讯作者Guo, Bin(guobin@simm.ac.cn) ; Xie, Xin() ; Hu, Wenhao(huwh90@mail.sysu.edu.cn)
英文摘要FFA1 (free fatty acid receptor 1) has emerged as an attractive antidiabetic target due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic beta cells with a low risk of hypoglycemia. Many reported FFA1 agonists possessed somewhat pharmacokinetic and/or safety issues. Herein, we describe the identification of 2,3-dihydrobenzo[b][1,4]dioxine as a novel scaffold for FFA1 agonists. Comprehensive structure-activity relationship study based on this scaffold led to the discovery of (S)-3-(4-(((S)-7-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl-methoxy) phenyl)hex-4-ynoic acid (26k), which displayed a potent FFA1 agonistic activity and good pharmacokinetic profiles. Subsequent in vivo studies demonstrated that compound 26k significantly improved the glucose tolerance in ICR mice. In summary, compound 26k is a promising drug candidate for further investigation.
WOS关键词RECEPTOR AGONISTS ; DISCOVERY ; ACIDS ; DRUGS ; GPR40 ; TAK-875
资助项目National Natural Science Foundation of China[21402222] ; National Natural Science Foundation of China[21332003] ; Personalized Medicines - Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of Chinese Academy of Sciences[XDA12040307] ; Youth Innovation Promotion Association of Chinese Academy of Sciences[2016262] ; Program for Guangdong Introducing Innovative and Entrepreneurial Teams[2016ZT06Y337]
WOS研究方向Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000458623500017
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/290421]  
专题新药研究国家重点实验室
通讯作者Guo, Bin; Xie, Xin; Hu, Wenhao
作者单位1.Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Guangdong, Peoples R China
2.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Sch Chem & Mol Engn, Shanghai 200062, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Natl Ctr Drug Screening, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Kong, Deyu,Guo, Shimeng,Yang, Yushe,et al. Synthesis and biological evaluation of novel potent FFA1 agonists containing 2,3-dihydrobenzo[b][1,4]dioxine[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2019,29(6):848-852.
APA Kong, Deyu,Guo, Shimeng,Yang, Yushe,Guo, Bin,Xie, Xin,&Hu, Wenhao.(2019).Synthesis and biological evaluation of novel potent FFA1 agonists containing 2,3-dihydrobenzo[b][1,4]dioxine.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,29(6),848-852.
MLA Kong, Deyu,et al."Synthesis and biological evaluation of novel potent FFA1 agonists containing 2,3-dihydrobenzo[b][1,4]dioxine".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 29.6(2019):848-852.

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来源：上海药物研究所

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