Skip to Main content Skip to Navigation
Journal articles

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.
Complete list of metadatas

Cited literature [60 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-02444610
Contributor : Sylvain Fraineau <>
Submitted on : Saturday, January 18, 2020 - 11:08:19 AM
Last modification on : Thursday, January 23, 2020 - 1:30:55 AM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

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⟩

Share

Metrics

Record views

41