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

Gur, Zehra Tugce; Caliskan, Burcu; Garscha, Ulrike; Olgac, Abdurrahman; Schubert, Ulrich S.; Gerstmeier, Jana; Werz, Oliver; Banoglu, Erden
Leukotrienes (LTs) and prostaglandin (PG)E2are enzymatically produced from arachidonic acid andrepresent highly bioactive lipid mediators with pro-inflammatory functions. Here, we report on novelmulti-target inhibitors that potently and dually interfere with 5-lipoxygenase-activating protein (FLAP)and microsomal prostaglandin E2synthase (mPGES)-1 in LT and PGE2biosynthesis, based on the pre-viously identified selective FLAP inhibitor BRP-7 (8,IC50¼ 0.31mM). C (5)-substitution of the benz-imidazole ring of BRP-7 by carboxylic acid and its bioisosteres provided compounds, exemplified by 57that potently suppress LT formation (IC50¼ 0.05mM) by targeting FLAP along with inhibition of mPGES-1(IC50¼ 0.42mM). Besides FLAP, also 5-lipoxygenase (5-LO) and LTC4synthase activities were inhibited by57 , albeit with lower potency (IC50¼ 0.6 and 6.2mM) than FLAP. Docking studies and molecul ar dynamicsimulations with FLAP, mPGES-1 and 5-LO provide valuable insights into potential binding interactions ofthe inhibitors with their targets. Together, these novel benzimidazole derivatives may possess potentialas le ads for development of effective anti-inflammatory drugs with multi-target properties for duallyinhibiting LT and PGE2production.
Type of Publication:
European Journal of Medicinal Chemistry
876 - 899