Jensen E, Bundgaard H
Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry, Copenhagen.
Acta Pharm Nord. 1991;3(4):243-7.
Various N-substituted 4-(aminomethyl)benzoate diesters of ganciclovir were synthesized and evaluated as prodrug forms with the aim of improving the delivery characteristics of ganciclovir. The esters were hydrolyzed enzymatically by human plasma to the parent drug, the hydrolysis proceeding through formation of the corresponding monoester. The nature of the amino substituents had a marked influence on the rate of enzymatic hydrolysis, the most enzymatically labile ester being the 4-(morpholinomethyl)benzoate derivative. All esters were more lipophilic than ganciclovir in terms of octanol-pH 7.4 buffer partition coefficients. These properties combined with good aqueous solubility and high chemical stability in weakly acidic solutions make the N-substituted 4-(aminomethyl)benzoate diesters a promising prodrug type for ganciclovir to enhance its delivery characteristics for e.g. parenteral administration.
合成了多种更昔洛韦的N-取代4-(氨甲基)苯甲酸二酯，并将其作为前药形式进行评估，目的是改善更昔洛韦的递送特性。这些酯在人血浆中被酶水解为母体药物，水解过程通过形成相应的单酯进行。氨基取代基的性质对酶促水解速率有显著影响，酶促水解最不稳定的酯是4-(吗啉甲基)苯甲酸酯衍生物。就辛醇-pH 7.4缓冲液分配系数而言，所有酯都比更昔洛韦更具亲脂性。这些特性与良好的水溶性和在弱酸性溶液中的高化学稳定性相结合，使得N-取代4-(氨甲基)苯甲酸二酯成为一种很有前景的更昔洛韦前药类型，可增强其递送特性，例如用于肠胃外给药。
