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Design, synthesis, and structure-activity relationship studies of 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole derivatives as necroptosis inhibitors

文献类型：期刊论文

作者Jin, Zechen2,4; Dai, Yang2,3; Ji, Yinchun3; Peng, Xia3; Duan, Wenhu1,2,4; Ai, Jing2,3; Zhang, Hefeng4
刊名RSC MEDICINAL CHEMISTRY
出版日期2024-07-17
卷号15期号:7页码:2514-2526
DOI10.1039/d4md00265b
通讯作者Ai, Jing(jai@simm.ac.cn) ; Zhang, Hefeng(zhanghefeng1@simm.ac.cn)
英文摘要The development of necroptosis inhibitors has emerged as a promising strategy to effectively mitigate necroptosis-related inflammatory diseases, neurodegenerative diseases, and cancers. In this paper, we reported a series of 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole derivatives as potent necroptosis inhibitors. The representative compound 26 displayed potent anti-necroptotic activity in both human and mouse cellular assays and exhibited potent inhibitory activity against receptor-interacting protein kinase 1 (RIPK1). In vivo pharmacokinetic studies were performed to determine the oral exposure of compound 26. Finally, molecular docking elucidated that compound 26 could effectively bind to the allosteric pocket of RIPK1 and serve as a type III inhibitor. Taken together, our findings highlighted that compound 26 represented a promising lead compound for future necroptosis inhibitor development.
WOS关键词CELL-DEATH ; KINASE ; RIP1 ; DISCOVERY ; PROGNOSIS ; PROTEIN
资助项目China Postdoctoral Science Foundation[2023T160663] ; China Postdoctoral Science Foundation[SIMM0320231002] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[81821005] ; Natural Science Foundation of China for Innovation Research Group[SIMM0120231001] ; Project of Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SYS202205] ; Shandong Laboratory Program
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001251974500001
出版者ROYAL SOC CHEMISTRY
源URL[http://119.78.100.183/handle/2S10ELR8/311944]  
专题中国科学院上海药物研究所
通讯作者Ai, Jing; Zhang, Hefeng
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, Sch Pharm, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Canc Res Ctr, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Small Mol Drug Res Ctr, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Jin, Zechen,Dai, Yang,Ji, Yinchun,et al. Design, synthesis, and structure-activity relationship studies of 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole derivatives as necroptosis inhibitors[J]. RSC MEDICINAL CHEMISTRY,2024,15(7):2514-2526.
APA Jin, Zechen.,Dai, Yang.,Ji, Yinchun.,Peng, Xia.,Duan, Wenhu.,...&Zhang, Hefeng.(2024).Design, synthesis, and structure-activity relationship studies of 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole derivatives as necroptosis inhibitors.RSC MEDICINAL CHEMISTRY,15(7),2514-2526.
MLA Jin, Zechen,et al."Design, synthesis, and structure-activity relationship studies of 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole derivatives as necroptosis inhibitors".RSC MEDICINAL CHEMISTRY 15.7(2024):2514-2526.

入库方式： OAI收割

来源：上海药物研究所

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