Synthesis, enzymatic hydrolysis and physico-chemical properties of N-substituted 4-(aminomethyl)benzoate diester prodrugs of ganciclovir.

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.