Riluzole prodrugs for melanoma and ALS: design, synthesis, and in vitro metabolic profiling.
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.
Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Road, Doylestown, PA 18902, USA.
Mark E
ME
McDonnell
Matthew D
MD
Vera
Benjamin E
BE
Blass
Jeffrey C
JC
Pelletier
Richard C
RC
King
Carmen
C
Fernandez-Metzler
Garry R
GR
Smith
Jay
J
Wrobel
Suzie
S
Chen
Brian A
BA
Wall
Allen B
AB
Reitz
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000378:metabolism; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019782:Riluzole / Q000097:blood / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*
D011355:Prodrugs; D019782:Riluzole; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2