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

Autor: He G; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.; University of Chinese Academy of Sciences, Beijing 100049, China., Zheng Y; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences, Beijing 100049, China., Chang S; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.; University of Chinese Academy of Sciences, Beijing 100049, China., Wang L; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai 201203, China., Yang X; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.; University of Chinese Academy of Sciences, Beijing 100049, China., Hao H; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Li J; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China., Zhang X; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Tian F; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Liang X; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences, Beijing 100049, China., Xu H; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Wang P; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Chen X; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Cao Z; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.; University of Chinese Academy of Sciences, Beijing 100049, China., Fang S; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Gao Z; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences, Beijing 100049, China.; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Liu H; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences, Beijing 100049, China.; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Aug 08; Vol. 67 (15), pp. 12912-12931. Date of Electronic Publication: 2024 Jul 22.
DOI: 10.1021/acs.jmedchem.4c00861
Abstrakt: 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 IC 50 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 ED 50 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 ED 50 value of 18.5 mg/kg. Overall, compounds 14 and 35 are promising leads for the development of new small-molecule therapeutics for epilepsy.
Databáze: MEDLINE