Discovery of novel 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as potent Nav1.1 activators.
Bioorg Med Chem Lett
; 29(6): 815-820, 2019 03 15.
Article
em En
| MEDLINE
| ID: mdl-30704812
ABSTRACT
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⯵M 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirrolidinas
/
Niacinamida
/
Descoberta de Drogas
/
Agonistas do Canal de Sódio Disparado por Voltagem
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2019
Tipo de documento:
Article