Riluzole prodrugs for melanoma and ALS: design, synthesis, and in vitro metabolic profiling.
Bioorg Med Chem
; 20(18): 5642-8, 2012 Sep 15.
Article
em En
| MEDLINE
| ID: mdl-22892214
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pró-Fármacos
/
Desenho de Fármacos
/
Riluzol
/
Esclerose Lateral Amiotrófica
/
Melanoma
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article