title: Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase-activating protein (FLAP).
abstract: Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand- and structure-based pharmacophore model led to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole (7) as developable candidate. Compound 7 potently suppressed leukotriene formation in intact neutrophils (IC(50)=0.31 μM) but essentially failed to directly inhibit 5-LO suggesting that interaction with FLAP causes inhibition of leukotriene synthesis. For structural optimization, a series of 46 benzimidazole-based derivatives of 7 were synthesized leading to more potent analogues (70-72, 82) with IC(50)=0.12-0.19 μM in intact neutrophils. Together, our results disclose the benzimidazole scaffold bearing an ibuprofen fingerprint as a new chemotype for further development of anti-leukotriene agents.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06330 Yenimahalle, Ankara, Turkey. banoglu@gazi.edu.tr
authors.forename: Erden
authors.initials: E
authors.lastname: Banoglu
authors.forename: Burcu
authors.initials: B
authors.lastname: Çalişkan
authors.forename: Susann
authors.initials: S
authors.lastname: Luderer
authors.forename: Gökçen
authors.initials: G
authors.lastname: Eren
authors.forename: Yagmur
authors.initials: Y
authors.lastname: Özkan
authors.forename: Wolfram
authors.initials: W
authors.lastname: Altenhofen
authors.forename: Christina
authors.initials: C
authors.lastname: Weinigel
authors.forename: Dagmar
authors.initials: D
authors.lastname: Barz
authors.forename: Jana
authors.initials: J
authors.lastname: Gerstmeier
authors.forename: Carlo
authors.initials: C
authors.lastname: Pergola
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000378:metabolism*; D001562:Benzimidazoles / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015289:Leukotrienes / Q000096:biosynthesis*; D008958:Models, Molecular; D015394:Molecular Structure; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D015289:Leukotrienes; D011994:Recombinant Proteins; C031000:benzimidazole