Discovery of novel 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as potent Nav1.1 activators

[Display omitted] 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 Io...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2019-03, Vol.29 (6), p.815-820
Main Authors: Miyazaki, Tohru, Kawasaki, Masanori, Suzuki, Atsushi, Ito, Yuki, Imanishi, Akio, Maru, Takamitsu, Kawamoto, Tomohiro, Koike, Tatsuki
Format: Article
Language:English
Subjects:
BBB penetration
Dravet syndrome
Nav1.1 activator
Slow current decay of inactivation
Voltage-gated sodium channels
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Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2019.01.023