Stability of alkoxycarbonylamidine prodrugs.

Autor: Shahrokh Z; Department of Pharmaceutical R&D, Genentech Inc., South San Francisco, California 94080, USA. zahra@gene.com, Lee E, Olivero AG, Matamoros RA, Robarge KD, Lee A, Weise KJ, Blackburn BK, Powell MF
Jazyk: angličtina
Zdroj: Pharmaceutical research [Pharm Res] 1998 Mar; Vol. 15 (3), pp. 434-41.
DOI: 10.1023/a:1011928415808
Abstrakt: 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.
Databáze: MEDLINE
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