Pro-drugs as drug delivery systems XVII. Esters of 4-hydroxybutyric acids as potential pro-drug types for γ-lactones

Abstract

The methyl and ethyl ester of 4-hydroxybutyric acid were prepared and evaluated as pro-drug models for the γ-lactone moiety occurring in several drugs such as pilocarpine. The esters were found to undergo a quantitative cyclization in neutral and alkaline aqueous solution at 37°C to γ-butyrolactone. The rates of lactonization were directly proportional to the hydroxide ion activity over the pH range studied (7.4–9.8) and the reactions appear to proceed by an intramolecular nucleophilic attack of alkoxide ion on the ester carbonyl moiety. Lactone formation proceeded rather slowly at pH 7.4 but was greatly accelerated in case of the corresponding phenyl ester according to a previous report. The ester derivatives are more lipophilic than the parent γ-butyrolactone as determined by partition experiments in a L-octanol-water system. It is suggested that esters, in particular aryl esters, of 4-hydroxybutyric acids may be potentially useful pro-drug candidates for agents containing a γ-lactone moiety, e.g. to facilitate biomembrane penetration through increased lipophilicity of the transport forms.