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


Creative Commons License

Pergola C., Gerstmeier J., Moench B., Caliskan B., Luderer S., Weinigel C., ...More

British Journal of Pharmacology, vol.171, no.12, pp.3051-3064, 2014 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 171 Issue: 12
  • Publication Date: 2014
  • Doi Number: 10.1111/bph.12625
  • Journal Name: British Journal of Pharmacology
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.3051-3064
  • Keywords: 5-lipoxygenase, 5-lipoxygenase activating protein, leukotriene, benzimidazole, inflammation, ARACHIDONIC-ACID, PHARMACOLOGICAL PROFILE, MEMBRANE-PROTEIN, GSK2190915, CELLS, CYCLOOXYGENASE, INVOLVEMENT, NEUTROPHILS, ACTIVATION, LICOFELONE
  • Gazi University Affiliated: Yes

Abstract

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 E2synthase-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. © 2014 The British Pharmacological Society.