Discovery of selective urokinase plasminogen activator (uPA) inhibitors as a potential treatment for multiple sclerosis

Bioorg Med Chem Lett. 2018 Nov 1;28(20):3372-3375. doi: 10.1016/j.bmcl.2018.09.001. Epub 2018 Sep 5.

Abstract

We report here the design and synthesis of a novel series of benzylamines that are potent and selective inhibitors of uPA with promising oral availability in rat. Further evaluation of one representative (ZK824859) of the new structural class showed that this compound lowered clinical scores when dosed in either acute or chronic mouse EAE models, suggesting that uPA inhibitors of this type could be useful for the treatment of multiple sclerosis.

Keywords: Multiple sclerosis; Serine protease; Urokinase; uPA; uPA inhibitor.

MeSH terms

  • Animals
  • Benzylamines / chemical synthesis
  • Benzylamines / chemistry
  • Benzylamines / pharmacokinetics
  • Benzylamines / therapeutic use*
  • Binding Sites
  • Female
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Multiple Sclerosis / drug therapy*
  • Rats
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacokinetics
  • Serine Proteinase Inhibitors / therapeutic use*
  • Structure-Activity Relationship
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors*
  • Urokinase-Type Plasminogen Activator / chemistry

Substances

  • Benzylamines
  • Serine Proteinase Inhibitors
  • Urokinase-Type Plasminogen Activator