Fluoroaromatic fragments on 1,3-disubstituted ureas enhance soluble epoxide hydrolase inhibition

[Display omitted] •Ureas with adamantane and fluoroaromatic fragments were studied as sEH inhibitors.•10 new ureas with IC50 up to 0.7 nM were synthesized.•Extra hydrogen bond between the fluorine atom and sEH discovered by X-Ray crystallography.•Found no effect of changes in the adamantyl on the el...

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Bibliographic Details
Published in:Journal of fluorine chemistry 2019-04, Vol.220, p.48-53
Main Authors: Burmistrov, Vladimir, Morisseau, Christophe, D’yachenko, Vladimir, Rybakov, Victor B., Butov, Gennady M., Hammock, Bruce D.
Format: Article
Language:English
Subjects:
Adamantane
Catalysis
Epoxide hydrolase
Fluorine
Fluoroaromatics
Hydrogen bonds
Inhibition
Inhibitor
Inhibitors
Soluble epoxide hydrolase
Staphylococcal enterotoxin H
Tyrosine
Urea
Ureas
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Summary:[Display omitted] •Ureas with adamantane and fluoroaromatic fragments were studied as sEH inhibitors.•10 new ureas with IC50 up to 0.7 nM were synthesized.•Extra hydrogen bond between the fluorine atom and sEH discovered by X-Ray crystallography.•Found no effect of changes in the adamantyl on the electron structure of the fluoroaromatic ring. A series of soluble epoxide hydrolase (sEH) inhibitors containing 2-fluorophenyl fragment was developed. Inhibition potency of the described compounds ranges from 0.7 to 630.9 nM. 1-(Adamantan-1-ylmethyl)-3-(2-fluorophenyl) urea (3b, IC50 = 0.7 nM) and 1-(adamantan-2-yl)-3-(2-fluorophenyl) urea (3i, IC50 = 1.0 nM) were found to be the most potent sEH inhibitors within the described series. Crystal results suggest that potency is probably enhanced by extra hydrogen bond between the fluorine atom and catalytic tyrosine residues.
ISSN:0022-1139
1873-3328
DOI:10.1016/j.jfluchem.2019.02.005