4,5-Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein (FLAP)

Eur J Med Chem. 2016 May 4:113:1-10. doi: 10.1016/j.ejmech.2016.02.027. Epub 2016 Feb 15.

Abstract

In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenase-activating protein (FLAP) based on the previously identified isoxazole derivative (8). The design and synthesis was directed towards a subset of 4,5-diaryl-isoxazole-3-carboxylic acid derivatives as LT biosynthesis inhibitors. Biological evaluation disclosed a new skeleton of potential anti-inflammatory agents, exemplified by 39 and 40, which potently inhibit cellular 5-LO product synthesis (IC50 = 0.24 μM, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 ≥ 8 μM). Docking studies and molecular dynamic simulations with 5-LO and FLAP provide valuable insights into potential binding modes of the inhibitors. Together, these diaryl-isoxazol-3-carboxylic acids may possess potential as leads for development of effective anti-inflammatory drugs through inhibition of LT biosynthesis.

Keywords: 5-lipoxygenase; 5-lipoxygenase-activating protein; Inflammation; Isoxazole; Leukotrienes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Lipoxygenase-Activating Protein Inhibitors / chemical synthesis
  • 5-Lipoxygenase-Activating Protein Inhibitors / chemistry
  • 5-Lipoxygenase-Activating Protein Inhibitors / pharmacology*
  • 5-Lipoxygenase-Activating Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Leukotrienes / biosynthesis*
  • Models, Molecular
  • Molecular Structure
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Structure-Activity Relationship

Substances

  • 5-Lipoxygenase-Activating Protein Inhibitors
  • 5-Lipoxygenase-Activating Proteins
  • Isoxazoles
  • Leukotrienes