期刊
BIOORGANIC CHEMISTRY
卷 98, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2020.103717
关键词
Voltage-gated sodium channel; Sodium channel blocker; Disopyramide; Drug discovery; Structure-activity relationships; Anticonvulsant agent; Refractory epilepsy; Drug repositioning; Medicinal Chemistry; Cardiac safety
资金
- Polish Ministry of Science and Higher Education [IP2012-008372]
- Ministry of Education, Youth and Sports of the Czech Republic (the National Sustainability Program I) [LO1503]
- Charles University [Q39]
- British Heart Foundation [PG/12/69/29784, PG/14/61/31015]
- Heart Research UK [RG2640]
A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据