RESUMEN
The preparation of the selective VEGF-R2 kinase inhibitor 10 (JNJ-17029259) is described in which the key precursor, 4-(5-isoxazolyl)benzonitrile, undergoes clean transformation to the corresponding cumylamine derivative with CeCl(3)-MeLi in THF. This high-yielding cerium mediated transformation is robust, reproducible, and readily scalable based on a requirement for the anhydrous CeCl(3) to be milled and subjected to ultrasound treatment prior to addition of methyllithium.
Asunto(s)
Cerio/química , Cesio/química , Cloruros/química , Compuestos de Litio/química , Nitrilos/química , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/síntesis química , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Ultrasonido , Benceno/química , Estructura Molecular , Nitrilos/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The series of 2-amino-4-aryl-5-chloropyrimidines was discovered to be potent for both VEGFR-2 and CDK1. Described here are the chemistry for analogue synthesis, SAR study, and its kinase selectivity prolifing. The full rat PK data and in vivo efficacy study are also included.
Asunto(s)
Proteína Quinasa CDC2/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A novel series of 4-aryl-5-cyano-2-aminopyrimidines were synthesized and found to have potent VEGF-R2 kinase inhibitory activity. Structure-activity relationships were investigated and compound 14a was shown to be efficacious in a mouse model of corneal neovascularization.