RESUMEN
Efforts toward developing orally bioavailable factor VIIa inhibitors starting from parenteral lead compound 1 are described. SAR resulted in improved physicochemical properties, leading to enhanced oral absorption in rat.
Asunto(s)
Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Factor VIIa/antagonistas & inhibidores , Trombosis/tratamiento farmacológico , Administración Oral , Animales , Disponibilidad Biológica , Ratas , Relación Estructura-Actividad , Trombina/antagonistas & inhibidoresRESUMEN
Within the trypsin family of coagulation proteases, obtaining highly selective inhibitors of factor VIIa has been challenging. We report a series of factor VIIa (fVIIa) inhibitors based on the 5-amidino-2-(2-hydroxy-biphenyl-3-yl)-benzimidazole (1) scaffold with potency for fVIIa and high selectivity against factors IIa, Xa, and trypsin. With this scaffold class, we propose that a unique hydrogen bond interaction between a hydroxyl on the distal ring of the biaryl system and the backbone carbonyl of fVIIa lysine-192 provides a basis for enhanced selectivity and potency for fVIIa.