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

Mark E. McDonnell, Matthew D. Vera, Benjamin E. Blass, Jeffrey C. Pelletier, Richard C. King, Carmen Fernandez-Metzler, Garry R. Smith, Jay Wrobel, Suzie Chen, Brian A. Wall, Allen B. Reitz

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5642-5648
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number18
DOIs
StatePublished - Sep 15 2012

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Keywords

  • Cancer
  • Cyp1A2
  • Melanoma
  • Prodrug
  • Riluzole

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