RESUMEN
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
Asunto(s)
Quinasa I-kappa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Quinolinas/química , Semicarbacidas/química , Tiourea/análogos & derivados , Animales , Perros , Femenino , Hepatocitos/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Quinasa I-kappa B/metabolismo , Macaca mulatta , Masculino , Ratones , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Semicarbacidas/síntesis química , Semicarbacidas/farmacocinética , Relación Estructura-Actividad , Tiourea/síntesis química , Tiourea/química , Tiourea/farmacocinéticaRESUMEN
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.
