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Discovery of a novel GPR35 agonist with high and equipotent species potency for oral treatment of IBD

文献类型：期刊论文

作者Song, Zhaoxiang3,6; Lu, Dan4,5; Sun, Jun3,5; Ye, Yangliang6; Fang, Jiahui5; Wang, Kai6; Guo, Shimeng5; Zhang, Qing1,2,5; He, Xinheng3; Xie, Xin1,2,3,4,5
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2023-12-15
卷号96页码:12
关键词GPR35 IBD Lodoxamide
ISSN号0968-0896
DOI10.1016/j.bmc.2023.117511
通讯作者Xie, Xin(xxie@simm.ac.cn) ; Shen, Jianhua(jhshen@simm.ac.cn)
英文摘要The G protein-coupled receptor 35 (GPR35) has been identified as a potential target in the treatment of inflammatory bowel disease (IBD). However, the lack of high and equipotent agonists on both human and mouse GPR35 has limited the in vivo study of GPR35 agonists in mouse models of IBD. In this study, structural modifications to lodoxamide provides a series of high and equivalent agonists on human, mouse, and rat GPR35. These molecules eliminate the species selectivity of human to mouse and rat orthologs that have been prevalent with GPR35 agonists including lodoxamide. The cLogP properties are also optimized to make the compounds more obedient to drug-like rules, yielding compound 4b (cLogP = 2.41), which activates human, mouse or rat GPR35 with EC50 values of 76.0, 63.7 and 77.8 nM, respectively. Oral administration of compound 4b at 20 mg/ kg alleviates clinical symptoms of DSS-induced IBD in mice, and is slightly more effective than 5-ASA at 200 mg/ kg. In summary, it can serve as a new start point for exploiting more potent GPR35 agonists without species differences for the treatment of IBD, and warrants further study.
WOS关键词PROTEIN-COUPLED RECEPTOR ; IDENTIFICATION ; ACID
资助项目National Natural Science Foundation of China[82073683] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82273764] ; National Natural Science Foundation of China[82030109]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:001113642000001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/308116]  
专题新药研究国家重点实验室
通讯作者Xie, Xin; Shen, Jianhua
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Chinese Acad Sci, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Song, Zhaoxiang,Lu, Dan,Sun, Jun,et al. Discovery of a novel GPR35 agonist with high and equipotent species potency for oral treatment of IBD[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2023,96:12.
APA Song, Zhaoxiang.,Lu, Dan.,Sun, Jun.,Ye, Yangliang.,Fang, Jiahui.,...&Shen, Jianhua.(2023).Discovery of a novel GPR35 agonist with high and equipotent species potency for oral treatment of IBD.BIOORGANIC & MEDICINAL CHEMISTRY,96,12.
MLA Song, Zhaoxiang,et al."Discovery of a novel GPR35 agonist with high and equipotent species potency for oral treatment of IBD".BIOORGANIC & MEDICINAL CHEMISTRY 96(2023):12.

入库方式： OAI收割

来源：上海药物研究所

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