RESUMEN
Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.
Asunto(s)
Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Descubrimiento de Drogas/métodos , Inhibidores del Factor Xa , Piridinas/síntesis química , Piridinas/farmacología , Administración Oral , Animales , Anticoagulantes/administración & dosificación , Benzamidas/administración & dosificación , Dominio Catalítico/efectos de los fármacos , Línea Celular , Perros , Relación Dosis-Respuesta a Droga , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/genética , Factor Xa/metabolismo , Humanos , Macaca fascicularis , Piridinas/administración & dosificación , Conejos , RatasRESUMEN
Anthranilamide-based benzamidine compound 4 and its N-substituted analogs were designed and examined as factor Xa inhibitors using substituted benzamidines as unconventional S4 binding element. A group of N,N-dialkylbenzamidines (11, 17 and 24) have been discovered as potent factor Xa inhibitors with strong anticoagulant activity and promising oral PK profiles.