Isoxazol-5(2H)-one: a new scaffold for potent human neutrophil elastase (HNE) inhibitors

J Enzyme Inhib Med Chem. 2017 Dec;32(1):821-831. doi: 10.1080/14756366.2017.1326915.

Abstract

Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure-activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2H)-one scaffold. The most potent compound (2o) had a good balance between HNE inhibitory activity (IC50 value =20 nM) and chemical stability in aqueous buffer (t1/2=8.9 h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE. Furthermore, since compounds 2o and 2s contain two carbonyl groups (2-N-CO and 5-CO) as possible points of attack for Ser195, the amino acid of the active site responsible for the nucleophilic attack, docking studies allowed us to clarify the different roles played by these groups.

Keywords: HNE inhibitor; Isoxazol-5(2H)-one; chemical stability; human neutrophil elastase; molecular docking.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Leukocyte Elastase / antagonists & inhibitors*
  • Leukocyte Elastase / metabolism
  • Molecular Structure
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Isoxazoles
  • Serine Proteinase Inhibitors
  • Leukocyte Elastase