Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Road, Doylestown, PA 18902, USA.
Bioorg Med Chem. 2012 Sep 15;20(18):5642-8. doi: 10.1016/j.bmc.2012.07.004. Epub 2012 Jul 21.
Riluzole (1) is an approved therapeutic for the treatment of ALS and has also demonstrated anti-melanoma activity in metabotropic glutamate GRM1 positive cell lines, a mouse xenograft assay and human clinical trials. Highly variable drug exposure following oral administration among patients, likely due to variable first pass effects from heterogeneous CYP1A2 expression, hinders its clinical use. In an effort to mitigate effects of this clearance pathway and uniformly administer riluzole at efficacious exposure levels, several classes of prodrugs of riluzole were designed, synthesized, and evaluated in multiple in vitro stability assays to predict in vivo drug levels. The optimal prodrug would possess the following profile: stability while transiting the digestive system, stability towards first pass metabolism, and metabolic lability in the plasma releasing riluzole. (S)-O-Benzyl serine derivative 9 was identified as the most promising therapeutically acceptable prodrug.
利鲁唑（1）是一种已批准用于治疗肌萎缩侧索硬化症的药物，并且在代谢型谷氨酸受体 GRM1 阳性细胞系、小鼠异种移植模型和人类临床试验中也显示出抗黑色素瘤活性。由于 CYP1A2 表达的异质性导致口服给药后患者的药物暴露高度可变，这可能会阻碍其临床应用。为了减轻这种清除途径的影响并以有效的暴露水平统一给予利鲁唑，设计、合成了几种利鲁唑前药，并在多个体外稳定性测定中进行了评估，以预测体内药物水平。最佳前药应具有以下特征：在消化系统转运过程中的稳定性、对首过代谢的稳定性以及在血浆中释放利鲁唑时的代谢不稳定性。（S）-O-苄基丝氨酸衍生物 9 被确定为最有前途的可接受的治疗性前药。
