Phosphoramidate derivates as controlled-release prodrugs of l-Dopa

l-Dopa has continued to be a mainstay in the symptomatic treatment of Parkinson's disease (PD). However, extensive peripheral metabolism, a short systemic circulation half-life and development of motor complications called dyskinesia prevents its long-term utilization as a PD therapeutic. Herein, we report a series of phosphoramidate derivatives of l-Dopa and controlled release of l-Dopa at pH 7.4 and 3. The kinetic data for the release of l-Dopa support our hypothesis that a proximal carboxylic acid can promote the pH-triggered hydrolysis of the phosphoramidate PN bond. As expected, esterification of the proximal carboxylic acid protects the scaffold from rapid release at low pH. This latter observation is particularly noteworthy as it suggests that the phosphoramidate-based l-Dopa-conjugate scaffold can be adapted for oral administration as an ester prodrug.