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

Jan Kramer 1 Stefano Woltersdorf 1 Thomas Duflot 2, 3 Kerstin Hiesinger 1 Felix Lillich 1 Felix Knoll 1 Sandra Wittmann 1 Franca-M Klingler 1 Steffen Brunst 1 Apirat Chaikuad 1 Christophe Morisseau 4 Bruce Hammock 4 Carola Buccellati 5 Angelo Sala 5 Enrico Rovati 5 Matthieu Leuillier 2 Sylvain Fraineau 2 Julie Rondeaux 2 Victor Hernandez-Olmos 1, 6 Jan Heering 1, 6 Daniel Merk 1 Denys Pogoryelov 1 Dieter Steinhilber 1 Stefan Knapp 1, 3 Jeremy Bellien 2, 3 Ewgenij Proschak 1
1 Goethe-University Frankfurt am Main
2 EnVI - Endothélium, valvulopathies et insuffisance cardiaque
3 CHU Rouen
4 UC Davis - University of California [Davis]
5 Università degli studi di Milano [Milano]
6 Fraunhofer IME - Fraunhofer Institute for Molecular Biology and Applied Ecology
Abstract : 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.
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Submitted on : Saturday, January 18, 2020 - 11:08:19 AM
Last modification on : Tuesday, June 16, 2020 - 2:02:02 PM
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Jan Kramer, Stefano Woltersdorf, Thomas Duflot, Kerstin Hiesinger, Felix Lillich, et al.. Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain. Journal of Medicinal Chemistry, American Chemical Society, 2019, 62 (18), pp.8443-8460. ⟨10.1021/acs.jmedchem.9b00445⟩. ⟨inserm-02444610⟩

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