Stability of alkoxycarbonylamidine prodrugs.
OBJECTIVE
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.
Shahrokh
Z
Z
Department of Pharmaceutical R&D, Genentech Inc., South San Francisco, California 94080, USA. zahra@gene.com
Lee
E
E
Olivero
A G
AG
Matamoros
R A
RA
Robarge
K D
KD
Lee
A
A
Weise
K J
KJ
Blackburn
B K
BK
Powell
M F
MF
D000578:Amidines / Q000737:chemistry*; D001569:Benzodiazepines / Q000737:chemistry*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D011355:Prodrugs / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship
D000578:Amidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; D001569:Benzodiazepines