Boosting Prodrug Stability

To increase the oral availability of certain therapeutic compounds, chemists will sometimes tack an ester group onto the molecule. These so-called prodrugs have a longer physiological lifetime, eventually reverting to the therapeutic form by hydrolyzing in the acidic environment of the stomach or the alkaline conditions in the intestines. The antiviral agent valacyclovir (GlaxoSmithKline's Valtrex), for example, is the L-valine ester of the parent compound acyclovir. According to a new report, drugmakers can maximize this type of prodrug's stability by employing cyclopropanecarboxylic acid esters (Org. Lett., DOI: 10.1021/ol702892e). A team led by James R. McCarthy of Eli Lilly & Co. and Kendall N. Houk of the University of California, Los Angeles, found that esters of cyclopropanecarboxylic acid are substantially more stable than other structurally related esters, presumably because of hyperconjugative stabilization. By making the cyclopropane amino acid ester of acyclovir (shown), the researchers were able to boost the compound's half-life at pH 6 to more than 300 hours. Valacyclovir, by comparison, has a half-life of only about 70 hours at pH 6.