RESUMO
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.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Pirazinas/química , Piridonas/química , Alanina/química , Desenho de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Mimetismo Molecular , Oligopeptídeos , Ligação Proteica , Pirazinas/farmacocinética , Piridonas/farmacocinética , Radioimunoensaio , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Oligopeptídeos/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Cães , Meia-Vida , Concentração Inibidora 50 , Taxa de Depuração Metabólica , Mimetismo Molecular , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
