Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase-activating protein (FLAP)

Bioorg Med Chem. 2012 Jun 15;20(12):3728-41. doi: 10.1016/j.bmc.2012.04.048. Epub 2012 May 1.

Abstract

Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand- and structure-based pharmacophore model led to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole (7) as developable candidate. Compound 7 potently suppressed leukotriene formation in intact neutrophils (IC(50)=0.31 μM) but essentially failed to directly inhibit 5-LO suggesting that interaction with FLAP causes inhibition of leukotriene synthesis. For structural optimization, a series of 46 benzimidazole-based derivatives of 7 were synthesized leading to more potent analogues (70-72, 82) with IC(50)=0.12-0.19 μM in intact neutrophils. Together, our results disclose the benzimidazole scaffold bearing an ibuprofen fingerprint as a new chemotype for further development of anti-leukotriene agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Lipoxygenase-Activating Proteins / metabolism*
  • Benzimidazoles / analysis*
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Drug Evaluation, Preclinical*
  • Enzyme Inhibitors / analysis*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Leukotrienes / biosynthesis*
  • Models, Molecular
  • Molecular Structure
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • 5-Lipoxygenase-Activating Proteins
  • ALOX5AP protein, human
  • Benzimidazoles
  • Enzyme Inhibitors
  • Leukotrienes
  • Recombinant Proteins
  • benzimidazole