RESUMEN
We herein disclose a novel chemical series of benzimidazole-ureas as inhibitors of VEGFR-2 and TIE-2 kinase receptors, both of which are implicated in angiogenesis. Structure-activity relationship (SAR) studies elucidated a critical role for the N1 nitrogen of both the benzimidazole (segment E) and urea (segment B) moieties. The SAR results were also supported by the X-ray crystallographic elucidation of the role of the N1 nitrogen and the urea moiety when the benzimidazole-urea compounds were bound to the VEGFR-2 enzyme. The left side phenyl ring (segment A) occupies the backpocket where a 3-hydrophobic substituent was favored for TIE-2 activity.
Asunto(s)
Bencimidazoles/síntesis química , Modelos Moleculares , Receptor TIE-2/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Bencimidazoles/química , Bencimidazoles/farmacología , Sitios de Unión , Cristalografía por Rayos X , Humanos , Ratones , Estructura Molecular , Células 3T3 NIH , Fosforilación , Receptor TIE-2/metabolismo , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/químicaRESUMEN
A novel series of anilinopyrazoles has been designed based on the X-ray crystal structure analysis. Most compounds from this series not only show sub-nanomolar IC(50) values for CDK2, but also demonstrate almost 1000-fold selectivity to other kinases including CDK1.