RESUMEN
Bicyclic pyrazinone and pyrimidinone amides were designed and synthesized as potent TF-FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of FVIIa prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent FVIIa potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity.
Asunto(s)
Amidas/química , Amidinas/síntesis química , Diseño de Fármacos , Factor VIIa/antagonistas & inhibidores , Pirazinas/química , Pirazinas/síntesis química , Pirimidinonas/química , Inhibidores de Serina Proteinasa/síntesis química , Amidas/síntesis química , Amidas/metabolismo , Amidinas/química , Amidinas/metabolismo , Sitios de Unión , Compuestos Bicíclicos con Puentes/química , Dominio Catalítico , Cristalografía por Rayos X , Factor VIIa/metabolismo , Unión Proteica , Pirazinas/metabolismo , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/metabolismo , Relación Estructura-ActividadRESUMEN
Herein we report the identification and evaluation of a novel series of (E)-3-(1-cyclohexyl-1H-pyrazol-3-yl)-2-methylacrylic acid derivatives identified from a deannulation study performed on the reported benzimidazole NS5B inhibitor, 1. This resulted in the identification of (E)-3-(2-(4-((4'-cyano-4-(4-hydroxypiperidine-1-carbonyl)biphenyl-2-yl)methoxy)phenyl)-1-cyclohexyl-1H-imidazol-4-yl)-2-methylacrylic acid (11) as a potent inhibitor of NS5B. Potential pathways for the further optimization of this series are suggested.