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Riluzole prodrugs for melanoma and ALS: design, synthesis, and in vitro metabolic profiling
Mark E McDonnell1, Matthew D Vera, Benjamin E Blass
1Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Road, Doylestown, PA 18902, USA.
Abstract:
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.
Insights
Researchers developed a new riluzole prodrug to ensure consistent drug levels for ALS patients. (S)-O-Benzyl serine derivative 9 shows promise for stable delivery and effective treatment.
Area of Science:
- Pharmacology
- Drug Development
- Oncology
Background:
- Riluzole is approved for Amyotrophic Lateral Sclerosis (ALS) and shows anti-melanoma effects.
- Variable oral drug exposure due to CYP1A2 metabolism hinders riluzole's clinical utility.
- Prodrug strategies aim to overcome first-pass metabolism and ensure uniform drug delivery.
Purpose of the Study:
- To design and synthesize novel riluzole prodrugs.
- To evaluate prodrug stability and predict in vivo drug release.
- To identify a prodrug with optimal characteristics for consistent riluzole administration.
Main Methods:
- Synthesis of various riluzole prodrug classes.
- In vitro stability assays to assess digestive and metabolic stability.
- Evaluation of prodrugs for plasma lability and riluzole release.
Main Results:
- Several prodrugs were synthesized and tested.
- The (S)-O-Benzyl serine derivative 9 demonstrated ideal stability and release properties.
- This prodrug is predicted to provide uniform and efficacious riluzole exposure.
Conclusions:
- Riluzole prodrugs can overcome variable pharmacokinetics caused by CYP1A2 metabolism.
- (S)-O-Benzyl serine derivative 9 is a promising candidate for improved riluzole therapy.
- This prodrug approach may enhance the clinical efficacy of riluzole in ALS and potentially melanoma treatment.
