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

22 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

Funding

We thank the National Institutes of Health [ 1R43NS057849 ], the ALS Association (TREAT program), the Department of Defense [AL093052] and the Veterans Administration at the Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA for their generous support of the research project. The authors are grateful to Dr. Michael Avram and Lynn Luong of the Northwestern University Clinical Pharmacology Core Facility and the Pharmaceutical Chemistry Translational Resource of the Center for Molecular Innovation and Drug Discovery for carrying out the LC–MS experiments for the blood–brain barrier penetration studies. Representative HTS hit compounds of ASP scaffold, data from in vitro ADME assays for ASP compounds, and the brain uptake study for compound 2 are available.

Keywords

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

ASJC Scopus subject areas

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

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