1. Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain
- Author
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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, and Proschak, Ewgenij
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Animals ,Binding Sites ,Catalytic Domain ,Drug Design ,Enzyme Inhibitors ,Epoxide Hydrolases ,Humans ,Ligands ,Male ,Oxazoles ,Phosphoric Monoester Hydrolases ,Rats ,Rats ,Sprague-Dawley ,Structure-Activity Relationship ,Temperature ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Medicinal & Biomolecular Chemistry ,Pharmacology and pharmaceutical sciences ,Medicinal and biomolecular chemistry ,Organic chemistry - 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.
- Published
- 2019