Identification of multi-target inhibitors of leukotriene and prostaglandin E 2 biosynthesis by structural tuning of the FLAP inhibitor BRP-7

Leukotrienes (LTs) and prostaglandin (PG)E are enzymatically produced from arachidonic acid and represent highly bioactive lipid mediators with pro-inflammatory functions. Here, we report on novel multi-target inhibitors that potently and dually interfere with 5-lipoxygenase-activating protein (FLAP...

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Veröffentlicht in:European journal of medicinal chemistry 2018-03, Vol.150, p.876
Hauptverfasser: Gür, Zehra Tuğçe, Çalışkan, Burcu, Garscha, UIrike, Olgaç, Abdurrahman, Schubert, Ulrich S, Gerstmeier, Jana, Werz, Oliver, Banoglu, Erden
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Sprache:eng
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Zusammenfassung:Leukotrienes (LTs) and prostaglandin (PG)E are enzymatically produced from arachidonic acid and represent highly bioactive lipid mediators with pro-inflammatory functions. Here, we report on novel multi-target inhibitors that potently and dually interfere with 5-lipoxygenase-activating protein (FLAP) and microsomal prostaglandin E synthase (mPGES)-1 in LT and PGE biosynthesis, based on the previously identified selective FLAP inhibitor BRP-7 (8, IC  = 0.31 μM). C (5)-substitution of the benzimidazole ring of BRP-7 by carboxylic acid and its bioisosteres provided compounds, exemplified by 57 that potently suppress LT formation (IC  = 0.05 μM) by targeting FLAP along with inhibition of mPGES-1 (IC  = 0.42 μM). Besides FLAP, also 5-lipoxygenase (5-LO) and LTC synthase activities were inhibited by 57, albeit with lower potency (IC  = 0.6 and 6.2 μM) than FLAP. Docking studies and molecular dynamic simulations with FLAP, mPGES-1 and 5-LO provide valuable insights into potential binding interactions of the inhibitors with their targets. Together, these novel benzimidazole derivatives may possess potential as leads for development of effective anti-inflammatory drugs with multi-target properties for dually inhibiting LT and PGE production.
ISSN:1768-3254