RESUMEN
HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Prolina/análogos & derivados , Silanos/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Relación Dosis-Respuesta a Droga , Genotipo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Silanos/farmacología , Relación Estructura-Actividad , Proteínas no Estructurales Virales/genética , Replicación Viral/efectos de los fármacosRESUMEN
Novel P2X(7) antagonists were developed using a purine scaffold. These compounds were potent and selective at the P2X(7) receptor in human and rodent as well as efficacious in rodent pain models. Compound 15a was identified to have oral potency in several pain models in rodent similar to naproxen, gabapentin and pregabalin. Structure-activity relationship (SAR) development and results of pain models are presented.
Asunto(s)
Dolor/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/síntesis química , Purinas/síntesis química , Receptores Purinérgicos P2X7/química , Animales , Humanos , Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/uso terapéutico , Purinas/química , Purinas/uso terapéutico , Ratas , Receptores Purinérgicos P2X7/metabolismo , Relación Estructura-ActividadRESUMEN
Structure-activity relationship (SAR) efforts around our initial lead compound 1 led to the identification of potent P2X(7) receptor antagonists with improved pharmacokinetic profiles. These compounds were potent and selective at the P2X(7) receptor in both human and rodent. Compound (entry 31) exhibited oral efficacy in the rat MIA and CCI pain models.
