Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase-activating protein (FLAP)

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• 作者：Erden Banoglu^a ; ^{banoglu@gazi.edu.tr} ; Burcu &Ccedil ; al谋艧kan^a ; Susann Luderer^b ; G&ouml ; k&ccedil ; en Eren^a ; Yagmur &Ouml ; zkan^a ; Wolfram Altenhofen^c ; ^&dagger ; ; Christina Weinigel^d ; Dagmar Barz^d ; Jana Gerstmeier^e ; Carlo Pergola^e ; Oliver Werz^e ; ^{Oliver.Werz@uni-jena.de}
• 关键词：AA ; arachidonic acid ; cPLA2 ; cytosolic phospholipase A2 ; FLAP ; 5-lipoxygenase-activating protein ; 5-HpETE ; 5-hydroperoxyeicosatetraenoic acid ; 5-LO ; 5-lipoxygenase ; LT ; leukotriene ; PGC buffer ; phosphate-buffered saline pH 7.4 containing 1  ; mg/mL gluc
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 June, 2012
• 卷：20
• 期：12
• 页码：3728-3741
• 文件大小：1324 K

摘要

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 (lass="boldFont">7) as developable candidate. Compound lass="boldFont">7 potently suppressed leukotriene formation in intact neutrophils (IC₅₀ = 0.31 渭M) 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 lass="boldFont">7 were synthesized leading to more potent analogues (lass="boldFont">70-lass="boldFont">72, lass="boldFont">82) with IC₅₀ = 0.12-0.19 渭M 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.