The novel benzimidazole derivative BRP-7 inhibits leukotriene biosynthesis in vitro and in vivo by targeting 5-lipoxygenase-activating protein (FLAP)

Br J Pharmacol. 2014 Jun;171(12):3051-64. doi: 10.1111/bph.12625.


Background and purpose: Leukotrienes (LTs) are inflammatory mediators produced via the 5-lipoxygenase (5-LOX) pathway and are linked to diverse disorders, including asthma, allergic rhinitis and cardiovascular diseases. We recently identified the benzimidazole derivative BRP-7 as chemotype for anti-LT agents by virtual screening targeting 5-LOX-activating protein (FLAP). Here, we aimed to reveal the in vitro and in vivo pharmacology of BRP-7 as an inhibitor of LT biosynthesis.

Experimental approach: We analysed LT formation and performed mechanistic studies in human neutrophils and monocytes, in human whole blood (HWB) and in cell-free assays. The effectiveness of BRP-7 in vivo was evaluated in rat carrageenan-induced pleurisy and mouse zymosan-induced peritonitis.

Key results: BRP-7 potently suppressed LT formation in neutrophils and monocytes and this was accompanied by impaired 5-LOX co-localization with FLAP. Neither the cellular viability nor the activity of 5-LOX in cell-free assays was affected by BRP-7, indicating that a functional FLAP is needed for BRP-7 to inhibit LTs, and FLAP bound to BRP-7 linked to a solid matrix. Compared with the FLAP inhibitor MK-886, BRP-7 did not significantly inhibit COX-1 or microsomal prostaglandin E2 synthase-1, implying the selectivity of BRP-7 for FLAP. Finally, BRP-7 was effective in HWB and impaired inflammation in vivo, in rat pleurisy and mouse peritonitis, along with reducing LT levels.

Conclusions and implications: BRP-7 potently suppresses LT biosynthesis by interacting with FLAP and exhibits anti-inflammatory effectiveness in vivo, with promising potential for further development.

Keywords: 5-lipoxygenase; 5-lipoxygenase activating protein; benzimidazole; inflammation; leukotriene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Lipoxygenase-Activating Protein Inhibitors / pharmacology*
  • 5-Lipoxygenase-Activating Proteins / metabolism
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Arachidonate 5-Lipoxygenase / metabolism
  • Benzimidazoles / pharmacology*
  • Carrageenan
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Humans
  • Leukotriene Antagonists / pharmacology*
  • Leukotrienes / biosynthesis*
  • Male
  • Mice
  • Monocytes / drug effects
  • Monocytes / enzymology
  • Neutrophils / drug effects
  • Neutrophils / enzymology
  • Peritonitis / chemically induced
  • Peritonitis / enzymology
  • Peritonitis / prevention & control
  • Pleurisy / chemically induced
  • Pleurisy / enzymology
  • Pleurisy / prevention & control
  • Rats, Wistar
  • Zymosan


  • 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole
  • 5-Lipoxygenase-Activating Protein Inhibitors
  • 5-Lipoxygenase-Activating Proteins
  • ALOX5AP protein, human
  • Alox5ap protein, mouse
  • Alox5ap protein, rat
  • Anti-Inflammatory Agents
  • Benzimidazoles
  • Leukotriene Antagonists
  • Leukotrienes
  • Carrageenan
  • Zymosan
  • Arachidonate 5-Lipoxygenase
  • ALOX5 protein, human