The novel benzimidazole derivative BRP-7 inhibits leukotriene biosynthesisin vitroandin vivoby targeting 5-lipoxygenase-activating protein (FLAP)

Autor: J Maczewsky, Dagmar Barz, Lidia Sautebin, Antonietta Rossi, Susann Luderer, Simona Pace, Christina Weinigel, Bettina Mönch, Jana Gerstmeier, Burcu Çalışkan, Carlo Pergola, Erden Banoglu, Oliver Werz
Rok vydání: 2014
Předmět:
Zdroj: British Journal of Pharmacology. 171:3051-3064
ISSN: 0007-1188
DOI: 10.1111/bph.12625
Popis: Background and Purpose Leukotrienes (LTs) are inflammatory mediators produced via the 5-lipoxygenase (5-LOX) pathway and are linked to diverse disorders, including asthma, allergic rhinitis and cardiovascular diseases. We recently identified the benzimidazole derivative BRP-7 as chemotype for anti-LT agents by virtual screening targeting 5-LOX-activating protein (FLAP). Here, we aimed to reveal the in vitro and in vivo pharmacology of BRP-7 as an inhibitor of LT biosynthesis. Experimental Approach We analysed LT formation and performed mechanistic studies in human neutrophils and monocytes, in human whole blood (HWB) and in cell-free assays. The effectiveness of BRP-7 in vivo was evaluated in rat carrageenan-induced pleurisy and mouse zymosan-induced peritonitis. Key Results BRP-7 potently suppressed LT formation in neutrophils and monocytes and this was accompanied by impaired 5-LOX co-localization with FLAP. Neither the cellular viability nor the activity of 5-LOX in cell-free assays was affected by BRP-7, indicating that a functional FLAP is needed for BRP-7 to inhibit LTs, and FLAP bound to BRP-7 linked to a solid matrix. Compared with the FLAP inhibitor MK-886, BRP-7 did not significantly inhibit COX-1 or microsomal prostaglandin E2 synthase-1, implying the selectivity of BRP-7 for FLAP. Finally, BRP-7 was effective in HWB and impaired inflammation in vivo, in rat pleurisy and mouse peritonitis, along with reducing LT levels. Conclusions and Implications BRP-7 potently suppresses LT biosynthesis by interacting with FLAP and exhibits anti-inflammatory effectiveness in vivo, with promising potential for further development.
Databáze: OpenAIRE
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