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Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious Glucagon-Like Peptide-1 Receptor Agonists

文献类型：期刊论文

作者Chen, Lili2,3; Yun, Ying1,3; Guo, Shimeng2; Wang, Xiaoyan2,3; Xiong, Muya2,3; Zhao, Tingting4; Xu, Tifei2; Shen, Jianhua2; Xie, Xin2; Wang, Kai2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-06-07
页码23
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c00320
通讯作者Xie, Xin(xxie@simm.ac.cn) ; Wang, Kai(kwang@simm.ac.cn)
英文摘要Danuglipron is the most representativesmall-molecule agonist ofthe glucagon-like peptide-1 receptor (GLP-1R) and has received considerableattention due to positive results in the treatment of type 2 diabetesmellitus (T2DM) and obesity in clinical trials. However, hERG inhibition,lower activity than endogenous GLP-1, and a short action time representlimitations in terms of feasible application. In this study, we reporta new class of 5,6-dihydro-1,2,4-triazine derivatives that serve toeliminate potential hERG inhibition caused by the piperidine ringof danuglipron. Applying systematic in vitro to in vivo screening,we have identified compound 42 as a highly potent andselective GLP-1R agonist, which delivers improved (7-fold) efficacyin stimulating cAMP accumulation compared with danuglipron and whichexhibits acceptable drug-like properties. Furthermore, 42 significantly reduces glucose excursion and inhibits food intakeof hGLP-1R Knock-In mice. These effects are longer-lasting than thatshown by danuglipron, demonstrating feasibility in the treatment ofT2DM and obesity.
WOS关键词GLP-1 RECEPTOR ; INSULIN-SECRETION ; ACTIVATION ; MECHANISMS ; OVERWEIGHT
资助项目Youth Innovation Promotion Association, Chinese Academy of Sciences[2019282] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82273764]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001006186400001
源URL[http://119.78.100.183/handle/2S10ELR8/306176]  
专题新药研究国家重点实验室
通讯作者Xie, Xin; Wang, Kai
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Lili,Yun, Ying,Guo, Shimeng,et al. Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious Glucagon-Like Peptide-1 Receptor Agonists[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023:23.
APA Chen, Lili.,Yun, Ying.,Guo, Shimeng.,Wang, Xiaoyan.,Xiong, Muya.,...&Wang, Kai.(2023).Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious Glucagon-Like Peptide-1 Receptor Agonists.JOURNAL OF MEDICINAL CHEMISTRY,23.
MLA Chen, Lili,et al."Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious Glucagon-Like Peptide-1 Receptor Agonists".JOURNAL OF MEDICINAL CHEMISTRY (2023):23.

入库方式： OAI收割

来源：上海药物研究所

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