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

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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Gür ZT,Çalışkan B,Garscha U,Olgaç A,Schubert US,Gerstmeier J,Werz O,Banoglu E

doi

10.1016/j.ejmech.2018.03.045

subject

Has Abstract

pub_date

2018-04-25 00:00:00

pages

876-899

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(18)30288-5

journal_volume

150

pub_type

杂志文章

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