RESUMEN
A number of novel fused thiophene derivatives have been prepared and identified as potent inhibitors of MEK. The SAR data of selected examples and the in vivo profiling of compound 13 h demonstrates the functional activity of this class of compounds in HT-29 PK/PD models.
Asunto(s)
Química Farmacéutica/métodos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Tiofenos/química , Animales , Línea Celular Tumoral , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Fosforilación , Electricidad Estática , Relación Estructura-Actividad , Factores de TiempoRESUMEN
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.