RESUMEN
The optimization of compounds from the 3-amido-4-anilinoquinolines series of CSF-1R kinase inhibitors is described. The series has excellent activity and kinase selectivity. Excellent physical properties and rodent PK profiles were achieved through the introduction of cyclic amines at the quinoline 6-position. Compounds with good activity in a mouse PD model measuring inhibition of pCSF-1R were identified.
Asunto(s)
Química Farmacéutica/métodos , Neoplasias/tratamiento farmacológico , Quinolinas/química , Quinolinas/farmacocinética , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Receptor de Factor Estimulante de Colonias de Macrófagos/química , Aminas/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Concentración 50 Inhibidora , Cinética , Ratones , Modelos Químicos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , RatasRESUMEN
A series of amidoheteroaryl compounds were designed and synthesized as inhibitors of B-Raf kinase. Several compounds from the series show excellent potency in biochemical, phenotypic and mode of action cellular assays. Potent examples from the series have also demonstrated good plasma exposure following an oral dose in rodents and activity against the Ras-Raf pathway in tumor bearing mice.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Mutación , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Administración Oral , Animales , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Ratas , Relación Estructura-Actividad , Quinasas raf/metabolismo , Proteínas ras/metabolismoRESUMEN
3-amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and SAR is reported, along with initial efforts to optimize the physical properties and PK through modifications at the quinoline 6- and 7-positions.
Asunto(s)
Química Farmacéutica/métodos , Neoplasias/tratamiento farmacológico , Quinolinas/química , Quinolinas/farmacocinética , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Receptor de Factor Estimulante de Colonias de Macrófagos/química , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , RatasRESUMEN
The bisamide class of kinase inhibitors was identified as being active against CSF-1R. The synthesis and SAR of pyridyl and thiazolyl bisamides are reported, along with the pharmacokinetic properties and in vivo activity of selected examples.
