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
Modifications to the basic side-chain of early lead structures of the indolyl quinolinone class of KDR kinase inhibitors resulted in improved pharmacokinetic and ancillary profiles. Specifically, compounds bearing 5-amido- and 5-sulphonamido-indolyl substituents exhibited lower plasma clearance and weaker binding affinity for the I(Kr) potassium channel hERG.
Asunto(s)
Proteínas de Transporte de Catión/metabolismo , Inhibidores Enzimáticos/farmacocinética , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/metabolismo , Quinolonas/farmacocinética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Línea Celular , Perros , Inhibidores Enzimáticos/química , Canales de Potasio Éter-A-Go-Go , Humanos , Microsomas Hepáticos/enzimología , Unión Proteica/fisiología , Quinolonas/química , Ratas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
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.
