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.

• MeSH
• antiflogistika chemie   farmakologie   MeSH
• bezbuněčný systém MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• inhibitory proteinu aktivujícího 5-lipoxygenasu chemie   farmakologie   MeSH
• leukotrieny biosyntéza   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• počítačová simulace MeSH
• preklinické hodnocení léčiv MeSH
• proteiny aktivující 5-lipoxygenasu metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiflogistika MeSH
• epoxid hydrolasy MeSH
• inhibitory enzymů MeSH
• inhibitory proteinu aktivujícího 5-lipoxygenasu MeSH
• leukotrieny MeSH
• proteiny aktivující 5-lipoxygenasu MeSH