Shahrokh Z, Lee E, Olivero A G, Matamoros R A, Robarge K D, Lee A, Weise K J, Blackburn B K, Powell M F
Department of Pharmaceutical R&D, Genentech Inc., South San Francisco, California 94080, USA.
Pharm Res. 1998 Mar;15(3):434-41. doi: 10.1023/a:1011928415808.
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.
Degradation was followed by RP-HPLC and rate constants were determined from a degradation scheme defined by product analysis.
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.
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.
采用烷氧羰基脒前药修饰法来掩盖精氨酸 - 甘氨酸 - 天冬氨酸拟肽中带正电荷的脒部分，并提高口服生物利用度。研究了乙氧羰基脒（ECA）、乙硫羰基脒（ETCA）和苯氧羰基脒（PCA）前药的水稳定性。
通过反相高效液相色谱法跟踪降解过程，并根据产物分析确定的降解方案测定速率常数。
ECA在pH约为7时具有最大稳定性，且在pH低于约4时与pH无关。在pH低于7时观察到ECA的一种新降解途径，即转化为乙氧羰基 - 氨基羰基。在pH低于7时，相对降解速率为ECA约等于ETCA < PCA，与取代脒基共轭酸的pKa降低顺序相同。ECA经碱催化裂解生成脒衍生物，其相对速率为ECA < ETCA < PCA，这与离去基团pKa的降低情况一致。
在所有pH值下观察到的速率常数足够小，以至于在肠道转运时间内预计只有5 - 30%（取决于取代基）的不良降解。预计在中性pH下，PCA前药向脒类药物的自发吸收后转化率比ECA前药高6倍。
