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Discovery of Novel Pyrimidine-Based Derivatives as Nav1.2 Inhibitors with Efficacy in Mouse Models of Epilepsy

文献类型：期刊论文

作者He, Guoxue5,6; Zheng, Yueming4,5; Chang, Shunzhen5,6; Wang, Long3,4; Yang, Xiaohao5,6; Hao, Haishuang4; Li, Jiyuan2; Zhang, Xian4; Tian, Fuyun1; Liang, Xuewu4,5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-07-22
卷号67期号:15页码:12912-12931
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00861
通讯作者Gao, Zhaobing(zbgao@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要Dysfunction of voltage-gated sodium channel Nav1.2 causes various epileptic disorders, and inhibition of the channel has emerged as an attractive therapeutic strategy. However, currently available Nav1.2 inhibitors exhibit low potency and limited structural diversity. In this study, a novel series of pyrimidine-based derivatives with Nav1.2 inhibitory activity were designed, synthesized, and evaluated. Compounds 14 and 35 exhibited potent activity against Nav1.2, boasting IC50 values of 120 and 65 nM, respectively. Compound 14 displayed favorable pharmacokinetics (F = 43%) following intraperitoneal injection and excellent brain penetration potency (B/P = 3.6). Compounds 14 and 35 exhibited robust antiepileptic activities in the maximal electroshock test, with ED50 values of 3.2 and 11.1 mg/kg, respectively. Compound 35 also demonstrated potent antiepileptic activity in a 6 Hz (32 mA) model, with an ED50 value of 18.5 mg/kg. Overall, compounds 14 and 35 are promising leads for the development of new small-molecule therapeutics for epilepsy.
WOS关键词SODIUM-CHANNEL BLOCKERS ; ANTICONVULSANT ACTIVITY ; BRAIN ; NA(V)1.2 ; THERAPY ; MECHANISMS ; EXPOSURE ; DRUGS
资助项目National Natural Science Foundation of China[82130105] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[92253305] ; National Natural Science Foundation of China[22337003] ; National Science Fund for Distinguished Young Scholars[81825021] ; Hangzhou institute for advanced study[2022ZZ01015] ; Hangzhou institute for advanced study[2022ZZ01012] ; Hangzhou institute for advanced study[2022ZZ01019]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001274533800001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/312517]  
专题新药研究国家重点实验室
通讯作者Gao, Zhaobing; Liu, Hong
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Fudan Univ, Human Phenome Inst, Pharmacophen Lab, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 He, Guoxue,Zheng, Yueming,Chang, Shunzhen,et al. Discovery of Novel Pyrimidine-Based Derivatives as Nav1.2 Inhibitors with Efficacy in Mouse Models of Epilepsy[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(15):12912-12931.
APA He, Guoxue.,Zheng, Yueming.,Chang, Shunzhen.,Wang, Long.,Yang, Xiaohao.,...&Liu, Hong.(2024).Discovery of Novel Pyrimidine-Based Derivatives as Nav1.2 Inhibitors with Efficacy in Mouse Models of Epilepsy.JOURNAL OF MEDICINAL CHEMISTRY,67(15),12912-12931.
MLA He, Guoxue,et al."Discovery of Novel Pyrimidine-Based Derivatives as Nav1.2 Inhibitors with Efficacy in Mouse Models of Epilepsy".JOURNAL OF MEDICINAL CHEMISTRY 67.15(2024):12912-12931.

入库方式： OAI收割

来源：上海药物研究所

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