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

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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https://www.hal.inserm.fr/inserm-02444610
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Submitted on : Saturday, January 18, 2020 - 11:08:19 AM
Last modification on : Thursday, August 4, 2022 - 10:09:01 AM
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Jan Kramer, Stefano Woltersdorf, Thomas Duflot, Kerstin Hiesinger, Felix F 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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