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

Authors: Kramer, Jan S; Woltersdorf, Stefano; Duflot, Thomas; Hiesinger, Kerstin; Lillich, Felix F; Knöll, Felix; Wittmann, Sandra K; Klingler, Franca-M; Brunst, Steffen; Chaikuad, Apirat; Morisseau, Christophe; Hammock, Bruce D; Buccellati, Carola; Sala, Angelo; Rovati, G Enrico; Leuillier, Matthieu; Fraineau, Sylvain; Rondeaux, Julie; Hernandez-Olmos, Victor; Heering, Jan; Merk, Daniel; Pogoryelov, Denys; Steinhilber, Dieter; Knapp, Stefan; Bellien, Jeremy; Proschak, Ewgenij

Published In J Med Chem, (2019 09 26)

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.

PubMed ID: 31436984 Exiting the NIEHS site

MeSH Terms: Animals; Binding Sites; Catalytic Domain; Drug Design; Enzyme Inhibitors/chemistry*; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/chemistry*; Humans; Ligands; Male; Oxazoles/chemistry; Phosphoric Monoester Hydrolases/chemistry; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Temperature

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