RESUMEN
Two novel series of small-molecule RGD mimetics containing either a substituted pyridone or pyrazinone central constraint were prepared. Modification of the beta-alanine 3-substituent produced compounds that are potent and selective alpha(v)beta(3) antagonists and exhibit a range of physicochemical properties.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Pirazinas/química , Piridonas/química , Alanina/química , Diseño de Fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Imitación Molecular , Oligopéptidos , Unión Proteica , Pirazinas/farmacocinética , Piridonas/farmacocinética , Radioinmunoensayo , Relación Estructura-ActividadRESUMEN
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared where deletion of an amide bond from an earlier series of linear RGD-mimetics provides a novel series of chain-shortened alpha(v)beta(3) antagonists with significantly improved oral pharmacokinetics. These chain-shortened alpha(v)beta(3) antagonists represent structurally novel integrin inhibitors.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Oligopéptidos/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Perros , Semivida , Concentración 50 Inhibidora , Tasa de Depuración Metabólica , Imitación Molecular , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacología , Relación Estructura-ActividadRESUMEN
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared incorporating various beta-amino acids as aspartic acid mimetics. Modification of the beta-alanine 3-substituents alters the potency and physicochemical properties of these receptor antagonists and in some cases provides orally bioavailable alpha(v)beta(3) inhibitors.