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Discovery of selective NaV1.8 inhibitors based on 5-chloro-2-(4,4-difluor- oazepan-1-yl)-6-methyl nicotinamide scaffold for the treatment of pain

文献类型：期刊论文

作者Qin, Hui2,3; Wei, Aihuan2; Wang, Yunqi1,4; Wang, Linlin1,4; Xu, Haiyan1; Zhan, Yan5; Tian, Xuechen2; Zheng, Yueming1,2,3; Gao, Zhaobing1,2,3,4; Hu, Youhong2,3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-06-05
卷号254页码:12
ISSN号0223-5234
关键词Pain Non-addictive analgesics Na V 1 8-selective inhibitors Bicyclic aromatic groups
DOI10.1016/j.ejmech.2023.115371
通讯作者Zheng, Yueming(zhengyueming@simm.ac.cn) ; Gao, Zhaobing(zbgao@simm.ac.cn) ; Hu, Youhong(yhhu@simm.ac.cn)
英文摘要The NaV1.8 channel is a genetically validated target for pain and it is mostly expressed in the peripheral nervous system. Based on the disclosed structures of NaV1.8-selective inhibitors, we designed and synthesized a series of compounds by introducing bicyclic aromatic fragments based on the nicotinamide scaffold. In this research, a systematic structure-activity relationship study was carried out. While compound 2c possessed moderate inhibitory activity (IC50 = 50.18 & PLUSMN; 0.04 nM) in HEK293 cells stably expressing human NaV1.8 channels, it showed potent inhibitory activity in DRG neurons and isoform selectivity (>200-fold against human NaV1.1, NaV1.5 and NaV1.7 channels). Moreover, the analgesic potency of compound 2c was identified in a post-surgical mouse model. These data demonstrate that compound 2c can be further evaluated as a non-addictive analgesic agent with reduced cardiac liabilities.
WOS关键词GATED SODIUM-CHANNELS
资助项目Lingang Laboratory[LG202103-01- 06] ; National Science Fund for Distinguished Young Scholars[81825021] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2020284]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:001013606800001
源URL[http://119.78.100.183/handle/2S10ELR8/306334]  
专题新药研究国家重点实验室
通讯作者Zheng, Yueming; Gao, Zhaobing; Hu, Youhong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Neurol & Psychiat Res & Drug Discovery, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 ZuChongZhi Rd, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100039, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Qin, Hui,Wei, Aihuan,Wang, Yunqi,et al. Discovery of selective NaV1.8 inhibitors based on 5-chloro-2-(4,4-difluor- oazepan-1-yl)-6-methyl nicotinamide scaffold for the treatment of pain[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,254:12.
APA Qin, Hui.,Wei, Aihuan.,Wang, Yunqi.,Wang, Linlin.,Xu, Haiyan.,...&Hu, Youhong.(2023).Discovery of selective NaV1.8 inhibitors based on 5-chloro-2-(4,4-difluor- oazepan-1-yl)-6-methyl nicotinamide scaffold for the treatment of pain.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,254,12.
MLA Qin, Hui,et al."Discovery of selective NaV1.8 inhibitors based on 5-chloro-2-(4,4-difluor- oazepan-1-yl)-6-methyl nicotinamide scaffold for the treatment of pain".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 254(2023):12.

入库方式： OAI收割

来源：上海药物研究所

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