title: Discovery of Potent Soluble Epoxide Hydrolase (sEH) Inhibitors by Pharmacophore-Based Virtual Screening.
abstract: There is an increasing interest in the development of soluble epoxide hydrolase (sEH) inhibitors, which block the degradation of endogenous anti-inflammatory epoxyeicosatrienoic acids. Within this study, a set of pharmacophore models for sEH inhibitors was developed. The Specs database was virtually screened and a cell-free sEH activity assay was used for the biological investigation of virtual hits. In total, out of 48 tested compounds, 19 were sEH inhibitors with IC50 < 10 μM, representing a prospective true positive hit rate of 40%. Six of these compounds displayed IC50 values in the low nanomolar range. The most potent compound 21, a urea derivative, inhibited sEH with an IC50 = 4.2 nM. The applied approach also enabled the identification of diverse chemical scaffolds, e.g. the pyrimidinone derivative 29 (IC50 = 277 nM). The generated pharmacophore model set therefore represents a valuable tool for the selection of compounds for biological testing.
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: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena , Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Garscha
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: Veronika
authors.initials: V
authors.lastname: Temml
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena , Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Josephine
authors.initials: J
authors.lastname: Liers
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena , Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
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
mesh_terms: D020134:Catalytic Domain; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D012995:Solubility; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D004851:Epoxide Hydrolases