Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA 4 Hydrolase

Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA hydrolase (LTA H) with submicromolar activity toward both targets has been designed and synthesized. Preli...

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Veröffentlicht in:ACS medicinal chemistry letters 2020-03, Vol.11 (3), p.298-302
Hauptverfasser: Hiesinger, Kerstin, Schott, Annika, Kramer, Jan S, Blöcher, René, Witt, Finja, Wittmann, Sandra K, Steinhilber, Dieter, Pogoryelov, Denys, Gerstmeier, Jana, Werz, Oliver, Proschak, Ewgenij
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container_end_page 302
container_issue 3
container_start_page 298
container_title ACS medicinal chemistry letters
container_volume 11
creator Hiesinger, Kerstin
Schott, Annika
Kramer, Jan S
Blöcher, René
Witt, Finja
Wittmann, Sandra K
Steinhilber, Dieter
Pogoryelov, Denys
Gerstmeier, Jana
Werz, Oliver
Proschak, Ewgenij
description Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA hydrolase (LTA H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure-activity relationship studies were performed to identify optimal substitution patterns. X-ray structure analysis of a promising dual inhibitor in complex with sEH, as well as molecular docking with LTA H provided a rationale for further optimization. Hereby, scaffold extension was successfully applied to yield potent dual sEH/LTA H inhibitors. The spectrum of pro- and anti-inflammatory lipid mediators was evaluated in M1 and M2 macrophages, stimulated with LPS, and incubated with the most promising compound . The effect of on the inflammatory lipid mediator profile characterizes dual sEH/LTA H inhibitors as an interesting option for future anti-inflammatory agent investigations.
doi_str_mv 10.1021/acsmedchemlett.9b00330
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title Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA 4 Hydrolase
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