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Discovery and optimization of novel indolecarboxylic acid derivative as potent glucagon-like peptide-1 receptor agonists

文献类型：期刊论文

作者Zhao, Wanting3; Yin, Yuqian3; Shi, Zhuo3; Yang, Ke2; Li, Xinglin2; Yang, Yushe1,2,3; Jing, Tongfei2; Kang, Zhenghui1,2,3
刊名MOLECULAR DIVERSITY
出版日期2025-05-14
页码23
关键词GLP-1R Agonists hERG Indolecarboxylic acid derivative T2DM Obesity
ISSN号1381-1991
DOI10.1007/s11030-025-11213-7
通讯作者Jing, Tongfei(jingtongfei0379@zidd.ac.cn) ; Kang, Zhenghui(kangzhenghui@simm.ac.cn)
英文摘要Several glucagon-like peptide-1 receptor (GLP-1R) agonists have been recognized as effective therapeutic strategies for T2DM and obesity. Our efforts focused on modifying the pyridine fragment and the region near the benzo[d]imidazole moiety of danuglipron to reduce the inhibitory activity on the hERG channel while preserving its ability to activate GLP-1R, leading to the synthesis of 21 novel derivatives. An optimized indolecarboxylic acid derivative, YK-11 (EC50 = 7.5 nM), showed promising ability in activating GLP-1R, with acceptable inhibition of the hERG ion channel (IC50 = 34.3 mu M). Furthermore, the docking analysis of YK-11 revealed that indolecarboxylic acid derivatives extended into the binding pocket of the GLP-1R protein in a similar manner to danuglipron, and the carboxyl group, methyl ester moiety, cyano group and cyclobutyl ether moiety of YKF-11 created four hydrogen bonds with Lys197, Gln221 and Arg299, respectively. This study provided alternative approach for the future development of GLP-1R agonists.
WOS关键词GLP-1 RECEPTOR ; ORAL SEMAGLUTIDE ; ACTIVATION
资助项目Financial support from Natural Science Foundation of Guangdong Province[2023A1515110403] ; Financial support from Natural Science Foundation of Guangdong Province[2024A1515030037] ; Natural Science Foundation of Guangdong Province[2023M743925] ; China Postdoctoral Science Foundation
WOS研究方向Biochemistry & Molecular Biology ; Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001488421500001
出版者SPRINGER
源URL[http://119.78.100.183/handle/2S10ELR8/317932]  
专题中国科学院上海药物研究所
通讯作者Jing, Tongfei; Kang, Zhenghui
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Zhao, Wanting,Yin, Yuqian,Shi, Zhuo,et al. Discovery and optimization of novel indolecarboxylic acid derivative as potent glucagon-like peptide-1 receptor agonists[J]. MOLECULAR DIVERSITY,2025:23.
APA Zhao, Wanting.,Yin, Yuqian.,Shi, Zhuo.,Yang, Ke.,Li, Xinglin.,...&Kang, Zhenghui.(2025).Discovery and optimization of novel indolecarboxylic acid derivative as potent glucagon-like peptide-1 receptor agonists.MOLECULAR DIVERSITY,23.
MLA Zhao, Wanting,et al."Discovery and optimization of novel indolecarboxylic acid derivative as potent glucagon-like peptide-1 receptor agonists".MOLECULAR DIVERSITY (2025):23.

入库方式： OAI收割

来源：上海药物研究所

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