Riluzole prodrugs for melanoma and ALS: Design, synthesis, and in vitro metabolic profiling

摘要: 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 human clinical trials. Highly variable drug exposure following oral administration among patients, likely due to first pass effects from heterogeneous CYP1A2 expression, hinders its use. In effort mitigate this clearance pathway uniformly administer riluzole at efficacious levels, several classes prodrugs were designed, synthesized, evaluated multiple vitro stability assays predict vivo levels. The optimal prodrug would possess profile: while transiting digestive system, towards metabolism, metabolic lability plasma releasing riluzole. (S)-O-Benzyl serine derivative 9 was identified as most promising therapeutically acceptable prodrug.