Development of novel small molecules for the treatment of ALS

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126950. doi: 10.1016/j.bmcl.2020.126950. Epub 2020 Jan 7.

Abstract

Amyotrophic lateral sclerosis (ALS) is a rare and progressive neurodegenerative disease with unknown etiology. It is caused by the degeneration of motor neurons responsible for controlling voluntary muscles. It has been reported that mutations in the superoxide dismutase (SOD) 1 gene can lead to ALS. SOD1 abnormalities have been identified in both familial, as well as sporadic ALS cases. SOD2 is a highly inducible SOD that works in conjunction with SOD1. SOD2 can be induced through activation of NF-κBs. We previously reported that the novel small molecule, SRI-22818, increases NF-κB expression and activation and SOD2 levels in vitro and has activity in vivo in the SOD1-G93A reference model of ALS. We report herein the synthesis and biological evaluation of SRI-22818 analogs.

Keywords: Amyotrophic Lateral Sclerosis (ALS); NF-κB; Small molecules; Superoxide dismutase (SOD).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology*
  • Gene Expression Regulation / drug effects
  • Humans
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use
  • Structure-Activity Relationship
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1 / genetics
  • Superoxide Dismutase-1 / metabolism

Substances

  • NF-kappa B
  • SOD1 protein, human
  • Small Molecule Libraries
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • superoxide dismutase 2