| Literature DB >> 31436984 |
Jan S Kramer1, Stefano Woltersdorf1, Thomas Duflot2,3, Kerstin Hiesinger1, Felix F Lillich1, Felix Knöll1, Sandra K Wittmann1, Franca-M Klingler1, Steffen Brunst1, Apirat Chaikuad1,4, Christophe Morisseau5, Bruce D Hammock5, Carola Buccellati6, Angelo Sala6, G Enrico Rovati6, Matthieu Leuillier3, Sylvain Fraineau3, Julie Rondeaux3, Victor Hernandez-Olmos1,7, Jan Heering1,7, Daniel Merk1, Denys Pogoryelov8, Dieter Steinhilber1, Stefan Knapp1,2, Jeremy Bellien3,9, Ewgenij Proschak1.
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.Entities:
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Year: 2019 PMID： 31436984 PMCID： PMC7262789 DOI： 10.1021/acs.jmedchem.9b00445
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446