Dipeptide Prodrugs of the Glutamate Modulator Riluzole

摘要

We have previously reported a prodrug strategy based on the marketed drug riluzole (2-amino-6-trifluoromethoxybenzothiazole), associated with the benefits of lower patient to patient variability of exposure and potentially once daily oral dosing, as opposed to the large variance and twice daily dosing, which is currently observed with the parent drug. Riluzole is a glutamate modulator that is currently approved by the US FDA to treat amyotrophic lateral sclerosis (ALS). Riluzole also strongly suppresses the growth of melanoma cells that express the type 1 metabotropic glutamate receptor (GRM1, mGluR1). Riluzole is a substrate for the variably expressed liver isozyme CYP1A2, which has been shown to contribute to the variance in exposure of riluzole in humans upon oral administration. In addition, an elevated Cmax following oral administration is a probable cause of increased liver enzyme levels in some patients. In order to mitigate these issues, a series of natural and unnatural dipeptide prodrugs of riluzole were prepared as products that bear lower first-pass hepatic clearance. The prodrugs were evaluated for their ability toproduce riluzole in serum while remaining intact prior to absorptionfrom the GI tract, characteristic of a type IIB prodrug. Here, wedescribe dipeptide conjugates of riluzole and report that the t-Bu-Gly-Sar-riluzole analog FC-3423 (>6) isabsorbed well and converts to riluzole in rats and mice in a regularand well-defined manner. FC-3423 strongly suppress tumor cell growthin mouse xenograft models of melanoma at a molar dose 10-fold lessthan that of riluzole itself.