RESUMEN
The 4-amino-5-azaindole as an amidino-benzimidazole replacement is described. A series of potent and selective analogs were discovered and showed desirable ex vivo efficacy as measured by PT.
Asunto(s)
Factor VIIa/antagonistas & inhibidores , Indoles/síntesis química , Indoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Factor VIIa/metabolismo , Indoles/química , Estructura Molecular , Piridinas/química , Relación Estructura-ActividadRESUMEN
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
The discovery and development of 5-azaindole factor VIIa inhibitors will be described.
Asunto(s)
Compuestos Aza/síntesis química , Compuestos Aza/farmacología , Factor VIIa/antagonistas & inhibidores , Indoles/síntesis química , Indoles/farmacología , Compuestos Aza/química , Cristalografía por Rayos X , Factor VIIa/química , Factor VIIa/metabolismo , Indoles/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Structure-activity relationships and binding mode of novel heterocyclic factor VIIa inhibitors will be described. In these inhibitors, a highly basic 5-amidinoindole moiety has been successfully replaced with a less basic 5-aminopyrrolo[3,2-b]pyridine scaffold.
Asunto(s)
Aminopiridinas/química , Factor VIIa/antagonistas & inhibidores , Fibrinolíticos/síntesis química , Compuestos Heterocíclicos/síntesis química , Tromboplastina/antagonistas & inhibidores , Aminopiridinas/farmacología , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Fibrinolíticos/farmacología , Compuestos Heterocíclicos/farmacología , Humanos , Relación Estructura-ActividadRESUMEN
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.