Arylazanylpyrazolone derivatives as inhibitors of mutant superoxide dismutase 1 dependent protein aggregation for the treatment of amyotrophic lateral sclerosis

Yinan Zhang, Radhia Benmohamed, He Huang, Tian Chen, Cindy Voisine, Richard I. Morimoto, Donald R. Kirsch, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2665-2675
Number of pages11
JournalJournal of Medicinal Chemistry
Volume56
Issue number6
DOIs
StatePublished - Mar 28 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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