Green asymmetric synthesis of epoxypeptidomimetics and evaluation as human cathepsin K inhibitors

Bioorg Med Chem. 2020 Aug 1;28(15):115597. doi: 10.1016/j.bmc.2020.115597. Epub 2020 Jun 17.

Abstract

Cathepsin K (CatK) is a cysteine protease known for its potent collagenolytic activity, being recognized as an important target to the development of therapies for the treatment of bone disorders. Epoxypeptidomimetics have been reported as potent inhibitors of cathepsins, thus in this work we present a green synthesis of new peptidomimetics by using a one-pot asymmetric epoxidation/Ugi multicomponent reaction. The compounds were evaluated against CatK showing selectivity when compared with cathepsin L, with an inhibition profile in the low micromolar IC50 range. Investigation of the mechanism of action carried out for compounds LSPN428 and LSPN694 suggested a mixed inhibition mode and docking studies allowed a better understanding about interactions of inhibitors with the enzyme.

Keywords: Cathepsin K; Cysteine proteases; Inhibitors; Peptidomimetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Cathepsin K / antagonists & inhibitors*
  • Cathepsin K / chemistry
  • Cathepsin K / metabolism
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry*
  • Cysteine Proteinase Inhibitors / metabolism
  • Epoxy Compounds / chemical synthesis
  • Epoxy Compounds / chemistry*
  • Epoxy Compounds / metabolism
  • Green Chemistry Technology
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / chemistry*
  • Peptidomimetics / metabolism
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Cysteine Proteinase Inhibitors
  • Epoxy Compounds
  • Peptidomimetics
  • CTSK protein, human
  • Cathepsin K