Water-Soluble, Solution-Stable, and Biolabile N-Substituted (Aminomethyl)benzoate Ester Prodrugs of Acyclovir

Abstract

Various N-substituted 3- or 4-(aminomethyl)benzoate esters of acyclovir were synthesized and evaluated as water-soluble prodrug forms with the aim of improving the delivery characteristics of acyclovir, in particular its parenteral administration. The esters showed a high solubility in weakly acidic solutions and, as demonstrated with the 3-(N,N-dipropylaminomethyl)benzoate ester, a high stability in such solutions, allowing storage for several years. The esters combine these properties with a high susceptibility to undergo enzymatic hydrolysis in plasma. The half-lives of hydrolysis in 80% human plasma ranged from 0.8 to 57 min, the rate being highly dependent on the position (3 or 4) of the aminomethyl group relative to the ester moiety. All esters were more lipophilic than acyclovir in terms of octanol–pH 7.4 buffer partition coefficients. These properties make N-substituted (aminomethyl)-benzoate esters a promising new prodrug type for acyclovir to enhance its delivery characteristics.