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Open AccessCommunication
Molecules 2017, 22(1), 45; doi:10.3390/molecules22010045

Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase

1
Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany
2
Institute of Pharmaceutical Biology, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany
3
Institute of Clinical Pharmacology, Goethe-University of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
*
Authors to whom correspondence should be addressed.
Academic Editor: Cornelis J. Van der Schyf
Received: 7 November 2016 / Revised: 15 December 2016 / Accepted: 23 December 2016 / Published: 29 December 2016
(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)
View Full-Text   |   Download PDF [1072 KB, uploaded 29 December 2016]   |  

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 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. View Full-Text
Keywords: soluble epoxide hydrolase; 5-lipoxygenase; inflammation; designed multitarget ligands; leukocyte-endothelial cell interaction soluble epoxide hydrolase; 5-lipoxygenase; inflammation; designed multitarget ligands; leukocyte-endothelial cell interaction
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Meirer, K.; Glatzel, D.; Kretschmer, S.; Wittmann, S.K.; Hartmann, M.; Blöcher, R.; Angioni, C.; Geisslinger, G.; Steinhilber, D.; Hofmann, B.; Fürst, R.; Proschak, E. Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase. Molecules 2017, 22, 45.

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