Unknown

Dataset Information

0

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 IC50 values of 200?nM in a cell-based FLAP test system and 20?nM for sEH activity in a cell-free assay.

SUBMITTER: Temml V 

PROVIDER: S-EPMC5317001 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Temml Veronika V   Garscha Ulrike U   Romp Erik E   Schubert Gregor G   Gerstmeier Jana J   Kutil Zsofia Z   Matuszczak Barbara B   Waltenberger Birgit B   Stuppner Hermann H   Werz Oliver O   Schuster Daniela D  

Scientific reports 20170220


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).  ...[more]

Similar Datasets

| S-EPMC5571211 | biostudies-other
| S-EPMC6155600 | biostudies-literature
| S-EPMC7262789 | biostudies-literature
| S-EPMC6210075 | biostudies-literature
| S-EPMC6168526 | biostudies-literature
| S-EPMC7073873 | biostudies-literature
| S-EPMC7004070 | biostudies-literature
| S-EPMC9583330 | biostudies-literature
| S-EPMC5933862 | biostudies-literature
| S-EPMC7942193 | biostudies-literature