Identification of aryl sulfonamides as novel and potent inhibitors of NaV1.5.
Bioorg Med Chem Lett
; 45: 128133, 2021 08 01.
Article
en En
| MEDLINE
| ID: mdl-34044121
ABSTRACT
We describe the synthesis and biological evaluation of a series of novel aryl sulfonamides that exhibit potent inhibition of NaV1.5. Unlike local anesthetics that are currently used for treatment of Long QT Syndrome 3 (LQT-3), the most potent compound (-)-6 in this series shows high selectivity over hERG and other cardiac ion channels and has a low brain to plasma ratio to minimize CNS side effects. Compound (-)-6 is also effective inshortening prolonged action potential durations (APDs) in a pharmacological model of LQT-3 syndrome in pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Unlike most aryl sulfonamide NaV inhibitors that bind to the channel voltage sensors, these NaV1.5 inhibitors bind to the local anesthetic binding site in the central pore of the channel.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Sulfonamidas
/
Canal de Sodio Activado por Voltaje NAV1.5
Tipo de estudio:
Diagnostic_studies
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2021
Tipo del documento:
Article