Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation. Targeting both LT biosynthesis and the conversion of EETs with a dual inhibitor of FLAP and sEH may represent a novel, powerful anti-inflammatory strategy. We present a pharmacophore-based virtual screening campaign that led to 20 hit compounds of which 4 targeted FLAP and 4 were sEH inhibitors. Among them, the first dual inhibitor for sEH and FLAP was identified, N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N'-(3,4-dichlorophenyl)urea with IC50 values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay.

Chair of Pharmaceutical Medicinal Chemistry University of Jena Philosophenweg 14 07743 Jena Germany

Institute of Pharmacy Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck University of Innsbruck Innrain 80 82 A 6020 Innsbruck Austria

Institute of Pharmacy Pharmacognosy and Center for Molecular Biosciences Innsbruck University of Innsbruck Innrain 80 82 A 6020 Innsbruck Austria

Laboratory of Plant Biotechnologies Institute of Experimental Botany AS CR Rozvojova 263 Prague 6 Lysolaje Czech Republic

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Structure-based molecular modeling in SAR analysis and lead optimization