Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase
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. I...
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MDPI AG
2016-12-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/22/1/45 |
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doaj-962d360e90ff4981ac1aaf0b035ac6b42020-11-24T20:57:48ZengMDPI AGMolecules1420-30492016-12-012214510.3390/molecules22010045molecules22010045Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide HydrolaseKarin Meirer0Daniel Glatzel1Simon Kretschmer2Sandra K. Wittmann3Markus Hartmann4René Blöcher5Carlo Angioni6Gerd Geisslinger7Dieter Steinhilber8Bettina Hofmann9Robert Fürst10Ewgenij Proschak11Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, GermanyInstitute of Pharmaceutical Biology, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, GermanyInstitute of Clinical Pharmacology, Goethe-University of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, GermanyInstitute of Clinical Pharmacology, Goethe-University of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, GermanyInstitute of Pharmaceutical Biology, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, GermanyThe 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 inhibitor KM55 was rationally designed and synthesized. KM55 was evaluated in enzyme activity assays with recombinant enzymes. Furthermore, activity of KM55 in human whole blood and endothelial cells was investigated. KM55 potently inhibited both enzymes in vitro and attenuated the formation of leukotrienes in human whole blood. KM55 was 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.http://www.mdpi.com/1420-3049/22/1/45soluble epoxide hydrolase5-lipoxygenaseinflammationdesigned multitarget ligandsleukocyte-endothelial cell interaction |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Karin Meirer Daniel Glatzel Simon Kretschmer Sandra K. Wittmann Markus Hartmann René Blöcher Carlo Angioni Gerd Geisslinger Dieter Steinhilber Bettina Hofmann Robert Fürst Ewgenij Proschak |
| spellingShingle |
Karin Meirer Daniel Glatzel Simon Kretschmer Sandra K. Wittmann Markus Hartmann René Blöcher Carlo Angioni Gerd Geisslinger Dieter Steinhilber Bettina Hofmann Robert Fürst Ewgenij Proschak Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase Molecules soluble epoxide hydrolase 5-lipoxygenase inflammation designed multitarget ligands leukocyte-endothelial cell interaction |
| author_facet |
Karin Meirer Daniel Glatzel Simon Kretschmer Sandra K. Wittmann Markus Hartmann René Blöcher Carlo Angioni Gerd Geisslinger Dieter Steinhilber Bettina Hofmann Robert Fürst Ewgenij Proschak |
| author_sort |
Karin Meirer |
| title |
Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase |
| title_short |
Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase |
| title_full |
Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase |
| title_fullStr |
Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase |
| title_full_unstemmed |
Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase |
| title_sort |
design, synthesis and cellular characterization of a dual inhibitor of 5-lipoxygenase and soluble epoxide hydrolase |
| publisher |
MDPI AG |
| series |
Molecules |
| issn |
1420-3049 |
| publishDate |
2016-12-01 |
| description |
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 inhibitor KM55 was rationally designed and synthesized. KM55 was evaluated in enzyme activity assays with recombinant enzymes. Furthermore, activity of KM55 in human whole blood and endothelial cells was investigated. KM55 potently inhibited both enzymes in vitro and attenuated the formation of leukotrienes in human whole blood. KM55 was 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. |
| topic |
soluble epoxide hydrolase 5-lipoxygenase inflammation designed multitarget ligands leukocyte-endothelial cell interaction |
| url |
http://www.mdpi.com/1420-3049/22/1/45 |
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