Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening

• DOI: 10.1038/srep42751
• Publication Date: 2017-02-20T10:37:17Z
• Authors: Veronika Temml; Ulrike Garscha; Erik Romp; Gregor Schubert; Jana Gerstmeier; Zsofia Kutil; Barbara Matuszczak; Birgit Waltenberger; Hermann Stuppner; Oliver Werz; Daniela Schuster
• Keywords: Epoxide hydrolase 2

Abstract 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 AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. soluble epoxide hydrolase (sEH) converts AA-derived epoxyeicosatrienoic acids (EETs) dihydroxyeicosatetraenoic (di-HETEs). Its consequently also counteracts inflammation. Targeting both conversion EETs a dual inhibitor sEH may represent novel, powerful strategy. We present pharmacophore-based virtual screening campaign that led 20 hit compounds which 4 targeted were inhibitors. Among them, first for was identified, N -[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]- ’-(3,4-dichlorophenyl)urea IC 50 values 200 nM cell-based test system activity cell-free assay.