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Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain

: Kramer, JS.; Woltersdorf, S.; Duflot, T.; Hiesinger, K.; Lillich, FF.; Knoll, F.; Wittmann, SK.; Klingler, FM.; Brunst, S.; Chaikuad, A.; Morisseau, C.; Hammock, BD.; Buccellati, C.; Sala, A.; Rovati, GE.; Leuillier, M.; Fraineau, S.; Rondeaux, J.; Hernandez-Olmos, V.; Heering, J.; Merk, D.; Pogoryelov, D.; Steinhilber, D.; Knapp, S.; Bellien, J.; Proschak, E.


Journal of medicinal chemistry 62 (2019), No.18, pp.8443-8460
ISSN: 0022-2623
ISSN: 1520-4804
Journal Article
Fraunhofer IME ()

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.