Physicochemical property modification strategies based on enzyme substrate specificities I: rationale, synthesis, and pharmaceutical properties of aspirin derivatives.

A rationale is developed for drug physicochemical property modification based on making derivatives that are substrates for known enzymes. The approach requires knowledge of the enzyme-substrate specificities to select the appropriate derivative. As a class, the digestive enzymes represent possible reconversion sites. It is shown that by using only known specificities of these enzymes, the physicochemical properties of a drug may be modified in almost any manner desired by appropriate derivative choice, with enzymatic regeneration remaining effective. The strategy is applied to making a stable aspirin derivative that is activated in vivo. Of the derivatives made, aspirin phenylalanine ethyl ester was shown to be stable in suspension form for over 4 years. It was also shown that aspirin is regenerated form the derivative in the presence of the enzymes alpha-chymotrypsin and carboxypeptidase in vitro. This biochemical approach to drug physicochemical property modification offers a new and powerful rationale for improving drug product efficacy.