STABILITY OF ALKOXYCARBONYLAMIDINE PRODRUGS

Purpose. Alkoxycarbonylamidine prodrug modification was used to mask t he positively-charged amidine moiety of an Arg-Gly-Asp peptidomimetic and enhance oral bioavailability. The aqueous stability of ethoxycarbo nylamidine (EGA), ethanethiocarbonylamidine (ETCA) and phenoxycarbonyl amidine (PCA) prodrugs was examined. Methods. Degradation was followed by RP-HPLC and rate constants were determined from a degradation sche me defined by product analysis. Results. ECA gave a pH of maximum stab ility at pH similar to 7 and was independent of pH below pH similar to 4. A novel degradation pathway of EGA, conversion to ethoxycarbonyl- aminocarbonyl, was observed below pH 7. The relative rates below pH 7 were ECA similar to ETCA<PCA, in the same order of decreasing pK(a) of the conjugate acid of the substituted amidino group. Base-catalyzed c leavage of ECA to yield the amidine derivative gave the relative rates ECA<ETCA<PCA, in agreement with the decreasing pK(a) of the leaving g roups. Conclusions. The observed rate constants at all pHs were small enough that only 5-30% (depending on the substituent) undesirable degr adation is predicted during transit time of the gut. The spontaneous p ostabsorptive conversion to the amidine drugs at neutral pH is predict ed to be 6x greater for the PCA than the ECA prodrugs.