ISSN:
1573-904X
Keywords:
peptidomimetic stability
;
alkoxycarbonylamidine
;
ester
;
prodrug
;
pH-rate profile
;
GPIIbIIIa
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Purpose. 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. Methods. Degradation was followed by RP-HPLC and rate constants were determined from a degradation scheme defined by product analysis. Results. 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~ETCA〈PCA, in the same order of decreasing pKa of the conjugate acid of the substituted amidino group. Base-catalyzed cleavage of EGA 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 EGA prodrugs.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1011928415808
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