RESUMEN
Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.
Asunto(s)
Antitrombina III/síntesis química , Antitrombina III/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Animales , Anticoagulantes/síntesis química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Antitrombina III/farmacocinética , Cristalografía por Rayos X , Perros , Humanos , Masculino , Piridonas/farmacocinética , Pirrolidinas/farmacocinética , Conejos , Ratas , Relación Estructura-ActividadRESUMEN
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.