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1.
Bioorg Med Chem Lett ; 20(16): 4951-4, 2010 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-20634071

RESUMEN

A series of analogues of the pyrazole lead 1 were synthesized in which the heterocyclic core was replaced with an imidazole. A number of potent antagonists were identified and structure-activity relationships (SAR) were investigated both with respect to activity at the P2X(7) receptor and in vitro metabolic stability. Compound 10 was identified as a potent P2X(7) antagonist with reduced in vitro metabolism and high solubility.


Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Imidazoles/química , Antagonistas del Receptor Purinérgico P2 , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Pirazoles/química , Ratas , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7 , Relación Estructura-Actividad
3.
Bioorg Med Chem Lett ; 20(15): 4653-6, 2010 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-20579878

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-Actividad
5.
Bioorg Med Chem Lett ; 20(17): 5080-4, 2010 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-20673717

RESUMEN

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.


Asunto(s)
Amidas/farmacología , Antagonistas del Receptor Purinérgico P2/farmacología , Ácido Pirrolidona Carboxílico/química , Receptores Purinérgicos P2X7/efectos de los fármacos , Amidas/química , Descubrimiento de Drogas , Modelos Moleculares , Antagonistas del Receptor Purinérgico P2/química , Relación Estructura-Actividad
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