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Bioorganic & medicinal chemistry (1)
Journal of biomolecular screening (1)
BLASS, BENJAMIN E. (1)
Blass, Benjamin E. (1)
CASSEL, JOEL A. (1)
Chen, Suzie (1)
Fernandez-Metzler, Carmen (1)
King, Richard C. (1)
McDonnell, Mark E. (1)
PAWLYK, AARON C. (1)
Pelletier, Jeffrey C. (1)
REITZ, ALLEN B. (1)
Reitz, Allen B. (1)
Smith, Garry R. (1)
Vera, Matthew D. (1)
Wrobel, Jay (1)
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Riluzole prodrugs for melanoma and ALS: design, synthesis, and in vitro metabolic profiling
McDonnell, Mark E.
Vera, Matthew D.
Pelletier, Jeffrey C.
King, Richard C.
Smith, Garry R.
Reitz, Allen B.
Bioorganic & medicinal chemistry
Riluzole (1) is an approved therapeutic for the treatment of ALS and has also demonstrated antimelanoma 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.
Riluzole; Prodrug; Cancer; Melanoma; Cyp1A2
Development of a Novel Nonradiometric Assay for Nucleic Acid Binding to TDP-43 Suitable for High-Throughput Screening Using AlphaScreen® Technology
CASSEL, JOEL A.
REITZ, ALLEN B.
PAWLYK, AARON C.
Journal of biomolecular screening
TAR DNA binding protein 43 (TDP-43) is a nucleic acid binding protein that is associated with the pathology of cystic fibrosis and neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. We have developed a robust, quantitative, nonradiometric high-throughput assay measuring oligonucleotide binding to TDP-43 using AlphaScreen® technology. Biotinylated single-stranded TAR DNA (bt-TAR-32) and 6 TG repeats (bt-TG6) bound with high affinity to TDP-43, with KD values of 0.75 nM and 0.63 nM, respectively. Both oligonucleotides exhibited slow dissociation rates, with half-lives of 750 min for bt-TAR-32 and 150 min for bt-TG6. The affinities of unlabeled oligonucleotides, as determined by displacement of either bt-TAR-32 or bt-TG6, were consistent with previous reports of nucleic acid interactions with TDP-43, where increasing TG or UG repeats yield greater affinity. A diversity library of 7360 compounds was screened for inhibition of TDP-43 binding to bt-TAR-32, and a series of compounds was discovered with nascent SAR and IC50 values ranging from 100 nM to 10 μM. These compounds may prove to be useful biochemical tools to elucidate the function of TDP-43 and may lead to novel therapeutics for indications where the TDP-43 nucleic acid interaction is causal to the associated pathology.
TDP-43; AlphaScreen; TAR DNA; ALS; cystic fibrosis
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