RESUMEN
Pyrimidino-thiazolyl carbonitriles were prepared that are potent VEGFR-2 (KDR) kinase inhibitors. The modification of lead structures resulted in 3m which exhibited the best overall profile in KDR inhibitory activity, iv/po pharmacokinetics, and reduced hERG affinity.
Asunto(s)
Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Perros , Macaca mulatta , Estructura Molecular , Nitrilos/química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Ratas , Sensibilidad y Especificidad , Relación Estructura-Actividad , Tiazoles/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.
Asunto(s)
Aminopiridinas/síntesis química , Canales de Potasio con Entrada de Voltaje/metabolismo , Piridinas/síntesis química , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Tiazoles/síntesis química , Administración Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacología , Animales , Disponibilidad Biológica , Línea Celular , Perros , Canal de Potasio ERG1 , Electrocardiografía/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go , Técnicas In Vitro , Pulmón/enzimología , Macaca mulatta , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Fosforilación , Piridinas/farmacocinética , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Tiazoles/farmacocinética , Tiazoles/farmacología , Distribución Tisular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
An azo-dye lead was modified to a novel N-(1,3-thiazol-2-yl)pyridin-2-amine series of KDR kinase inhibitors through the use of rapid analog libraries. This new class has been found to be potent, selective, and of low molecular weight. Molecular modeling has postulated an interesting conformational preference and binding mode for these compounds in the active site of the enzyme.
Asunto(s)
Aminas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Aminas/síntesis química , Sitios de Unión , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Unión Proteica , Conformación Proteica/efectos de los fármacos , Relación Estructura-Actividad , Termodinámica , Receptor 2 de Factores de Crecimiento Endotelial Vascular/químicaRESUMEN
1,5-Diarylbenzimidazoles have been identified as potent inhibitors of KDR kinase activity. The series was developed with a goal of finding compounds with optimal drug-like properties. This communication describes structural modifications in the series that enhance solubility, lower protein binding, and provide compounds with excellent potency and pharmacokinetic profiles.