Arylsulfanyl pyrazolones block mutant SOD1-G93A aggregation. Potential application for the treatment of amyotrophic lateral sclerosis

Tian Chen, Radhia Benmohamed, Anthony C. Arvanites, Hantamalala Ralay Ranaivo, Richard I Morimoto, Robert J. Ferrante, D Martin Watterson, Donald R. Kirsch, Richard B Silverman

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. Mutations in copper/zinc superoxide dismutase 1 (SOD1) have been implicated in the pathophysiology of this disease. Using a high-throughput screening assay expressing mutant G93A SOD1, two bioactive chemical hit compounds (1 and 2), identified as arylsulfanyl pyrazolones, were identified. The structural optimization of this scaffold led to the generation of a more potent analogue (19) with an EC50 of 170 nM. To determine the suitability of this class of compounds for further optimization, 1 was subjected to a battery of pharmacokinetic assays; most of the properties of 1 were good for a screening hit, except it had a relatively rapid clearance and short microsomal half-life stability. Compound 2 was found to be blood-brain barrier penetrating with a brain/plasma ratio = 0.19. The optimization of this class of compounds could produce novel therapeutic candidates for ALS patients.

Original languageEnglish (US)
Pages (from-to)613-622
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2011

Keywords

  • Amyotrophic lateral sclerosis
  • Arylsulfanyl pyrazolone
  • Blood-brain barrier penetration
  • Mutant G93A SOD1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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