Department of Chemistry, Washington State University, Pullman, WA 99164, USA.
Department of Chemistry, Washington State University, Pullman, WA 99164, USA.
Bioorg Med Chem Lett. 2019 Sep 15;29(18):2571-2574. doi: 10.1016/j.bmcl.2019.08.005. Epub 2019 Aug 5.
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.
左旋多巴一直是治疗帕金森病（PD）症状的主要药物。然而，广泛的外周代谢、短的系统循环半衰期和运动并发症（称为运动障碍）的发展，阻止了其作为 PD 治疗药物的长期应用。在此，我们报告了一系列的 l-Dopa 磷酰胺酯衍生物，并在 pH 值为 7.4 和 3 时控制 l-Dopa 的释放。l-Dopa 释放的动力学数据支持了我们的假设，即近端羧酸可以促进磷酰胺酯 PN 键的 pH 触发水解。正如预期的那样，近端羧酸的酯化保护了支架免受低 pH 下的快速释放。这一观察结果尤其值得注意，因为它表明基于磷酰胺酯的 l-Dopa 缀合物支架可以被改编为口服酯前药。
