RESUMEN
Aurora kinases are cell cycle regulated serine/threonine kinases that have been linked to cancer. Compound 1 was identified as a potent Aurora inhibitor but lacked oral bioavailability. Optimization of 1 led to the discovery of a series of fluoroamine and deuterated analogues, exemplified by compound 25, with an improved pharmacokinetic profile. We found that blocking oxidative metabolism at the benzylic position and decreasing the basicity of the amine are important to obtaining compounds with good biological profiles and oral bioavailability.
Asunto(s)
Antineoplásicos/síntesis química , Flúor , Imidazoles/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazinas/síntesis química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Aurora Quinasas , Disponibilidad Biológica , Línea Celular Tumoral , Deuterio , Perros , Ensayos de Selección de Medicamentos Antitumorales , Histonas/metabolismo , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Macaca fascicularis , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Fosforilación , Pirazinas/farmacocinética , Pirazinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.
