Stability of Alkoxycarbonylamidine Prodrugs

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Alkoxycarbonylamidine prodrug modification was used to mask the positively-charged amidine moiety of an Arg-Gly-Asp pepti-domimetic and enhance oral bioavailability. The aqueous stability of ethoxycarbonylamidine (EGA), ethanethiocarbonylamidine (ETCA) and phenoxycarbonylamidine (PCA) prodrugs was examined.


Degradation was followed by RP-HPLC and rate constants were determined from a degradation scheme defined by product analysis.


EGA gave a pH of maximum stability at pH ∼7 and was independent of pH below pH ∼4. A novel degradation pathway of EGA, conversion to ethoxycarbonyl- aminocarbonyl, was observed below pH 7. The relative rates below pH 7 were ECA~ETCAConclusions

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 EGA prodrugs.

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