Open AccessDesign of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA4 Hydrolase
Author(s) -
Kerstin Hiesinger,
Annika Schott,
Jan S. Kramer,
René Blöcher,
Finja Witt,
Sandra K. Wittmann,
Dieter Steinhilber,
Denys Pogoryelov,
Jana Gerstmeier,
Oliver Werz,
Ewgenij Proschak
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00330
Subject(s) - epoxide hydrolase 2 , epoxide hydrolase , chemistry , hydrolase , docking (animal) , arachidonic acid , yield (engineering) , pharmacology , combinatorial chemistry , enzyme , biochemistry , medicine , materials science , nursing , metallurgy , microsome
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 4 hydrolase (LTA 4 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 4 H provided a rationale for further optimization. Hereby, scaffold extension was successfully applied to yield potent dual sEH/LTA 4 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 14 . The effect of 14 on the inflammatory lipid mediator profile characterizes dual sEH/LTA 4 H inhibitors as an interesting option for future anti-inflammatory agent investigations.