Exploring chemical substructures essential for HERG k(+) channel blockade by synthesis and biological evaluation of dofetilide analogues.
ChemMedChem
; 4(10): 1722-32, 2009 Oct.
Article
en En
| MEDLINE
| ID: mdl-19725081
ABSTRACT
In this study we followed a new approach to analyze molecular substructures required for hERG channel blockade. We designed and synthesized 40 analogues of dofetilide (1), a potent hERG potassium channel blocker, and established structure-activity relationships (SAR) for their interaction with this important cardiotoxicity-related off-target. Structural modifications to dofetilide were made by diversifying the substituents on the phenyl rings and the protonated nitrogen and by varying the carbon chain length. The analogues were evaluated in a radioligand binding assay and SAR data were derived with the aim to specify structural features that give rise to hERG toxicity.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fenetilaminas
/
Sulfonamidas
/
Diseño de Fármacos
/
Bloqueadores de los Canales de Potasio
/
Canales de Potasio Éter-A-Go-Go
Límite:
Humans
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2009
Tipo del documento:
Article