Open AccessDiscovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain
Author(s) -
Jan S. Kramer,
Stefano Woltersdorf,
Thomas Duflot,
Kerstin Hiesinger,
Felix F Lillich,
Felix Knöll,
Sandra K. Wittmann,
FrancaMaria Klingler,
Steffen Brunst,
A. Chaikuad,
Christophe Morisseau,
Bruce D. Hammock,
Carola Buccellati,
Angelo Sala,
G. Enrico Rovati,
Matthieu Leuillier,
Sylvain Fraineau,
Julie Rondeaux,
Víctor HernándezOlmos,
Jan Heering,
Daniel Merk,
Denys Pogoryelov,
Dieter Steinhilber,
Stefan Knapp,
Jérémy Bellien,
Ewgenij Proschak
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b00445
Subject(s) - epoxide hydrolase 2 , chemistry , in vivo , hydrolase , enzyme , active site , biochemistry , phosphatase , acid phosphatase , in vitro , stereochemistry , biology , microbiology and biotechnology
The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure-activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid ( 22b , SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo.