title: Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening.
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 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 IC50values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay.
authors.affiliation: Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.|Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Temml
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, University of Jena, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Garscha
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, University of Jena, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Romp
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, University of Jena, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Schubert
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, University of Jena, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Gerstmeier
authors.affiliation: Laboratory of Plant Biotechnologies, Institute of Experimental Botany AS CR, Rozvojova 263, Prague 6 - Lysolaje, Czech Republic.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kutil
authors.affiliation: Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Matuszczak
authors.affiliation: Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Waltenberger
authors.affiliation: Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
authors.forename: Hermann
authors.initials: H
authors.lastname: Stuppner
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, University of Jena, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000737:chemistry / Q000494:pharmacology; D058927:5-Lipoxygenase-Activating Proteins / Q000378:metabolism*; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology; D002474:Cell-Free System; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D015289:Leukotrienes / Q000096:biosynthesis; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D058946:5-Lipoxygenase-Activating Protein Inhibitors; D058927:5-Lipoxygenase-Activating Proteins; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D015289:Leukotrienes; D004851:Epoxide Hydrolases