PEPTIDE ESTERS AS WATER-SOLUBLE PRODRUGS FOR HYDROXYL CONTAINING AGENTS - CHEMICAL-STABILITY AND ENZYMATIC-HYDROLYSIS OF BENZYL-ESTERS OF GLYCINE, DIGLYCINE AND TRIGLYCINE
PEPTIDE ESTERS AS WATER-SOLUBLE PRODRUGS FOR HYDROXYL CONTAINING AGENTS - CHEMICAL-STABILITY AND ENZYMATIC-HYDROLYSIS OF BENZYL-ESTERS OF GLYCINE, DIGLYCINE AND TRIGLYCINE
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DOI：
10.1016/0378-5173(91)90073-w
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发表时间：
1991-04-22
影响因子：
5.8
通讯作者：
BUNDGAARD, H
中科院分区：
文献类型：
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作者：
JENSEN, E;BUNDGAARD, H
研究了苯甲醇的单、二和甘油三酯的化学稳定性和酶解，以评估肽酯作为含有羟基的药物的水溶性前药的潜在用途。所有酯在80%的人血浆中容易水解生成苯甲醇，甘氨酸酯的半衰期为69分钟，二甘氨酸酯为17分钟，三甘氨酸酯为58分钟。后一种酯的水解以二甘氨酸酯为中间体进行两步反应。在60℃条件下，得到了酯类化合物在水溶液中降解的ph值曲线。最大的稳定性发生在pH 3-4，在这个pH值下酯是高度水溶性的。二甘酸酯和甘油三酯在pH值3 ~ 5时的稳定性无显著差异，仅略高于甘氨酸酯。因此，二肽和三肽酯前药在化学稳定性方面似乎并不比α -氨基酸酯具有显著优势。根据温度加速研究，甘油三酯水溶液（pH值4）的保质期（10%）在25℃下预计只有8天。
The chemical stability and enzymatic hydrolysis of the mono-, di- and triglycine esters of benzyl alcohol were studied to assess the potential usefulness of peptide esters as water-soluble prodrugs for agents containing a hydroxyl group. All esters were readily hydrolyzed in 80% human plasma to give benzyl alcohol, the half-lives being 69 min for the glycine ester, 17 min for the diglycine ester and 58 min for the triglycine ester. The hydrolysis of the latter ester occurred by a two step reaction with the diglycine ester as an intermediate. The pH-rate profiles for the degradation of the esters in aqueous solution were obtained at 60-degrees-C. Maximal stability occurred at pH 3-4 at which pH the esters are highly water-soluble. The stability of the di- and triglycine esters at pH 3-5 were not markedly different and only slightly higher than that of the glycine ester. Therefore, di- and tripeptide ester prodrugs do not appear to possess significant advantages over alpha-amino acid esters in terms of chemical stability. From temperature-accelerated studies, the shelf-life (t10%) of an aqueous soluiton (pH 4) of the triglycine ester was thus predicted to be only 8 days at 25-degrees-C.