Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine.
Bioorg Med Chem Lett
; 26(13): 3202-3206, 2016 07 01.
Article
en En
| MEDLINE
| ID: mdl-27080178
ABSTRACT
We started with a medium throughput screen of heterocyclic compounds without basic amine groups to avoid hERG and ß-blocker activity and identified [1,2,4]triazolo[4,3-a]pyridine as an early lead. Optimization of substituents for Late INa current inhibition and lack of Peak INa inhibition led to the discovery of 4h (GS-458967) with improved anti-arrhythmic activity relative to ranolazine. Unfortunately, 4h demonstrated use dependent block across the sodium isoforms including the central and peripheral nervous system isoforms that is consistent with its low therapeutic index (approximately 5-fold in rat, 3-fold in dog). Compound 4h represents our initial foray into a 2nd generation Late INa inhibitor program and is an important proof-of-concept compound. We will provide additional reports on addressing the CNS challenge in a follow-up communication.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piridinas
/
Triazoles
/
Bloqueadores de los Canales de Sodio
/
Descubrimiento de Drogas
/
Canal de Sodio Activado por Voltaje NAV1.5
/
Ranolazina
/
Corazón
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos