RESUMEN
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.
