title: Arylazanylpyrazolone derivatives as inhibitors of mutant superoxide dismutase 1 dependent protein aggregation for the treatment of amyotrophic lateral sclerosis.
abstract: The arylsulfanylpyrazolone and aryloxanylpyrazolone scaffolds previously were reported to inhibit Cu/Zn superoxide dismutase 1 dependent protein aggregation and to extend survival in the ALS mouse model. However, further evaluation of these compounds indicated weak pharmacokinetic properties and a relatively low maximum tolerated dose. On the basis of an ADME analysis, a new series of compounds, the arylazanylpyrazolones, has been synthesized, and structure-activity relationships were determined. The SAR results showed that the pyrazolone ring is critical to cellular protection. The NMR, IR, and computational analyses suggest that phenol-type tautomers of the pyrazolone ring are the active pharmacophore with the arylazanylpyrazolone analogues. A comparison of experimental and calculated IR spectra is shown to be a valuable method to identify the predominant tautomer.
authors: Department of Chemistry and Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University , Evanston, Illinois 60208-3113, USA.
authors: Yinan
authors: Y
authors: Zhang
authors: Radhia
authors: R
authors: Benmohamed
authors: He
authors: H
authors: Huang
authors: Tian
authors: T
authors: Chen
authors: Cindy
authors: C
authors: Voisine
authors: Richard I
authors: RI
authors: Morimoto
authors: Donald R
authors: DR
authors: Kirsch
authors: Richard B
authors: RB
authors: Silverman
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D018938:Caco-2 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D047069:Pyrazolones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D047069:Pyrazolones; C000606290:SOD1 protein, human; C038362:pyrazolone; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1