RESUMEN
Structure-activity relationships (SAR) of analogues of lead compound 1 were investigated and compound 16 was selected for further study in animal models of pain. Compound 16 was shown to be a potent antihyperalgesic agent in both the rat acute complete Freund's adjuvant (CFA) model of inflammatory pain [Iadarola, M. J.; Douglass, J.; Civelli, O.; Naranjo, J. R. rain Res.1988, 455, 205] and the knee joint model of chronic inflammatory pain [Wilson, A. W.; Medhurst, S. J.; Dixon, C. I.; Bontoft, N. C.; Winyard, L. A.; Brackenborough, K. T.; De Alba, J.; Clarke, C. J.; Gunthorpe, M. J.; Hicks, G. A.; Bountra, C.; McQueen, D. S.; Chessell, I. P. Eur. J. Pain2006, 10, 537].
Asunto(s)
Acetamidas/química , Antagonistas del Receptor Purinérgico P2X , Pirazoles/química , Acetamidas/síntesis química , Acetamidas/uso terapéutico , Administración Oral , Animales , Modelos Animales de Enfermedad , Humanos , Dolor/tratamiento farmacológico , Pirazoles/síntesis química , Ratas , Receptores Purinérgicos P2X7/metabolismo , Relación Estructura-ActividadRESUMEN
High-throughput screening identified compound 1 as a potent P2X(7) receptor antagonist suitable for lead optimisation. Structure-activity relationships (SAR) of a series of (1H-pyrazol-4-yl)acetamides were investigated and compound 32 was identified as a potent P2X(7) antagonist with enhanced potency and favourable physicochemical and pharmacokinetic properties.
Asunto(s)
Acetamidas/química , Antiinfecciosos/síntesis química , Antagonistas del Receptor Purinérgico P2 , Pirazoles/síntesis química , Acetamidas/síntesis química , Acetamidas/farmacocinética , Administración Oral , Animales , Antiinfecciosos/química , Antiinfecciosos/farmacocinética , Ensayos Analíticos de Alto Rendimiento , Humanos , Inyecciones Intravenosas , Pirazoles/química , Pirazoles/farmacocinética , Ratas , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7 , Relación Estructura-ActividadRESUMEN
A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.
Asunto(s)
Imidazolinas/farmacología , Antagonistas Purinérgicos/farmacología , Receptores Purinérgicos P2X7/efectos de los fármacos , Administración Oral , Animales , Disponibilidad Biológica , Semivida , Haplorrinos , Imidazolinas/administración & dosificación , Imidazolinas/química , Imidazolinas/farmacocinética , Antagonistas Purinérgicos/administración & dosificación , Antagonistas Purinérgicos/química , Antagonistas Purinérgicos/farmacocinética , RatasRESUMEN
A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.