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J Med Chem. 2019 Sep 26;62(18):8443-8460. doi: 10.1021/acs.jmedchem.9b00445. Epub 2019 Sep 17.

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

Author information

1
Institute of Pharmaceutical Chemistry , Goethe-University Frankfurt , Max-von-Laue-Strasse 9 , 60438 Frankfurt am Main , Germany.
2
Laboratory of Pharmacokinetics, Toxicology and Pharmacogenetics , Rouen University Hospital , 76000 Rouen , France.
3
Normandie Université, UNIROUEN, INSERM U1096 , 1 rue de Germont , 76000 Rouen , France.
4
Structural Genomics Consortium, Buchmann Institute for Life Sciences , Goethe-University Frankfurt , Max-von-Laue-Strasse 15 , 60438 Frankfurt am Main , Germany.
5
Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center , University of California Davis , Davis , California 95616 , United States.
6
Department of Pharmacological and Biomolecular Sciences , University of Milan , Via Balzaretti 9 , 20133 Milan , Italy.
7
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP , Theodor-Stern-Kai 7 , 60596 Frankfurt am Main , Germany.
8
Institute of Biochemistry , Goethe-University Frankfurt , Max-von-Laue-Strasse 9 , 60438 Frankfurt am Main , Germany.
9
Department of Clinical Pharmacology , Rouen University Hospital , 76000 Rouen , France.

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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