Discovery of novel 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as potent Nav1.1 activators.,Bioorganic & Medicinal Chemistry Letters

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Discovery of novel 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as potent Nav1.1 activators.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2019-01-23 , DOI: 10.1016/j.bmcl.2019.01.023
Tohru Miyazaki ₁ , Masanori Kawasaki ₁ , Atsushi Suzuki ₁ , Yuki Ito ₁ , Akio Imanishi ₁ , Takamitsu Maru ₂ , Tomohiro Kawamoto ₂ , Tatsuki Koike ₁

Affiliation

The voltage-gated sodium channel, Nav1.1, is predominantly expressed in parvalbumin-positive fast spiking interneurons and has been genetically linked to Dravet syndrome. Starting from a high throughput screening hit isoxazole derivative 5, modifications of 5 via combinations of IonWorks and Q-patch assays successfully identified the nicotinamide derivative 4. Its increasing decay time constant (tau) of Nav1.1 currents at 0.03 μM along with significant selectivity against Nav1.2, Nav1.5, and Nav1.6 and acceptable brain exposure in mice was observed. Compound 4 is a promising Nav1.1 activator that can be used to analyze pathophysiological functions of the Nav1.1 channel towards treating various central nervous system diseases.

中文翻译：

发现新型的4-苯基-2-（吡咯烷基）烟酰胺衍生物作为有效的Nav1.1活化剂。

电压门控钠通道Nav1.1主要在小白蛋白阳性快速加标中间神经元中表达，并与Dravet综合征遗传相关。从高通量筛选命中的异恶唑衍生物5开始，通过结合IonWorks和Q-patch分析对5进行修饰，成功鉴定出烟酰胺衍生物4。其Nav1.1电流在0.03μM时的增加的衰减时间常数（tau）以及显着的选择性小鼠对Nav1.2，Nav1.5和Nav1.6的抵抗力和可接受的大脑暴露情况都可以观察到。化合物4是一种很有前途的Nav1.1激活剂，可用于分析Nav1.1通道的病理生理功能，以治疗各种中枢神经系统疾病。

更新日期：2019-01-23

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