title: Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase.
abstract: The arachidonic acid cascade is a key player in inflammation, and numerous well-established drugs interfere with this pathway. Previous studies have suggested that simultaneous inhibition of 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH) results in synergistic anti-inflammatory effects. In this study, a novel prototype of a dual 5-LO/sEH inhibitorKM55was rationally designed and synthesized.KM55was evaluated in enzyme activity assays with recombinant enzymes. Furthermore, activity ofKM55in human whole blood and endothelial cells was investigated.KM55potently inhibited both enzymes in vitro and attenuated the formation of leukotrienes in human whole blood.KM55was also tested in a cell function-based assay. The compound significantly inhibited the LPS-induced adhesion of leukocytes to endothelial cells by blocking leukocyte activation.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany. karin.meirer@boehringer-ingelheim.com.
authors.forename: Karin
authors.initials: K
authors.lastname: Meirer
authors.affiliation: Institute of Pharmaceutical Biology, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany. Glatzel@em.uni-frankfurt.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Glatzel
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany. simkrets@pharmchem.uni-frankfurt.de.
authors.forename: Simon
authors.initials: S
authors.lastname: Kretschmer
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany. wittmann@pharmchem.uni-frankfurt.de.
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Wittmann
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany. hartmann@pharmchem.uni-frankfurt.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Hartmann
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany. bloecher@ucdavis.edu.
authors.forename: René
authors.initials: R
authors.lastname: Blöcher
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. angioni@em.uni-frankfurt.de.
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. geisslinger@em.uni-frankfurt.de.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany. steinhilber@em.uni-frankfurt.de.
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany. hofmann@pharmchem.uni-frankfurt.de.
authors.forename: Bettina
authors.initials: B
authors.lastname: Hofmann
authors.affiliation: Institute of Pharmaceutical Biology, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany. fuerst@em.uni-frankfurt.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Fürst
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany. proschak@pharmchem.uni-frankfurt.de.
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D007962:Leukocytes / Q000378:metabolism; D015289:Leukotrienes / Q000096:biosynthesis; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C000618775:1-(3-(5-(hydroxyureido)methyl-2-methoxyphenoxy)propyl)-3-(4-(trifluoromethoxy)phenyl)urea; D000893:Anti-Inflammatory Agents; D006845:Hydrocarbons, Fluorinated; D015289:Leukotrienes; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D014508:Urea; D001094:Arachidonate 5-Lipoxygenase; D004851:Epoxide Hydrolases
keywords: 5-lipoxygenase; designed multitarget ligands; inflammation; leukocyte-endothelial cell interaction; soluble epoxide hydrolase