2. Academic Validation
  3. Identification of multi-target inhibitors of leukotriene and prostaglandin E2 biosynthesis by structural tuning of the FLAP inhibitor BRP-7

Identification of multi-target inhibitors of leukotriene and prostaglandin E2 biosynthesis by structural tuning of the FLAP inhibitor BRP-7

  • Eur J Med Chem. 2018 Apr 25:150:876-899. doi: 10.1016/j.ejmech.2018.03.045.
Zehra Tuğçe Gür 1,  Burcu Çalışkan 1,  UIrike Garscha 2,  Abdurrahman Olgaç 1,  Ulrich S Schubert 3,  Jana Gerstmeier 2,  Oliver Werz 4,  Erden Banoglu 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330, Ankara, Turkey.
  • 2 Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743, Ena, Germany.
  • 3 Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743, Jena, Germany; Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, D-07743 Jena, Germany.
  • 4 Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743, Ena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743, Jena, Germany.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330, Ankara, Turkey. Electronic address: [email protected].
PMID: 29597170 DOI: 10.1016/j.ejmech.2018.03.045
Abstract

Leukotrienes (LTs) and prostaglandin (PG)E2 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 E2 synthase (mPGES)-1 in LT and PGE2 biosynthesis, based on the previously identified selective FLAP Inhibitor BRP-7 (8, IC50 = 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 (IC50 = 0.05 μM) by targeting FLAP along with inhibition of mPGES-1 (IC50 = 0.42 μM). Besides FLAP, also 5-lipoxygenase (5-LO) and LTC4 synthase activities were inhibited by 57, albeit with lower potency (IC50 = 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 PGE2 production.

Keywords

5-Lipoxygenase; 5-Lipoxygenase-activating protein; Benzimidazole; Inflammation; Leukotriene; Microsomal prostaglandin E(2) synthase-1.

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