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Pharm Res ; 15(3): 434-41, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9563074

RESUMO

PURPOSE: Alkoxycarbonylamidine prodrug modification was used to mask the positively-charged amidine moiety of an Arg-Gly-Asp peptidomimetic and enhance oral bioavailability. The aqueous stability of ethoxycarbonylamidine (ECA), ethanethiocarbonylamidine (ETCA) and phenoxycarbonylamidine (PCA) prodrugs was examined. METHODS: Degradation was followed by RP-HPLC and rate constants were determined from a degradation scheme defined by product analysis. RESULTS: ECA gave a pH of maximum stability at pH approximately 7 and was independent of pH below pH approximately 4. A novel degradation pathway of ECA, conversion to ethoxycarbonyl- aminocarbonyl, was observed below pH 7. The relative rates below pH 7 were ECA approximately ETCA < PCA, in the same order of decreasing pKa of the conjugate acid of the substituted amidino group. Base-catalyzed cleavage of ECA to yield the amidine derivative gave the relative rates ECA < ETCA < PCA, in agreement with the decreasing pKa of the leaving groups. CONCLUSIONS: The observed rate constants at all pHs were small enough that only 5-30% (depending on the substituent) undesirable degradation is predicted during transit time of the gut. The spontaneous post-absorptive conversion to the amidine drugs at neutral pH is predicted to be 6x greater for the PCA than the ECA prodrugs.


Assuntos
Amidinas/química , Benzodiazepinas/química , Inibidores da Agregação Plaquetária/química , Pró-Fármacos/química , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Solubilidade , Relação Estrutura-Atividade
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