2. Academic Validation
  3. Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain

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

  • J Med Chem. 2019 Sep 26;62(18):8443-8460. doi: 10.1021/acs.jmedchem.9b00445.
Jan S Kramer 1,  Stefano Woltersdorf 1,  Thomas Duflot 2 3,  Kerstin Hiesinger 1,  Felix F Lillich 1,  Felix Knöll 1,  Sandra K Wittmann 1,  Franca-M Klingler 1,  Steffen Brunst 1,  Apirat Chaikuad 1 4,  Christophe Morisseau 5,  Bruce D Hammock 5,  Carola Buccellati 6,  Angelo Sala 6,  G Enrico Rovati 6,  Matthieu Leuillier 3,  Sylvain Fraineau 3,  Julie Rondeaux 3,  Victor Hernandez-Olmos 1 7,  Jan Heering 1 7,  Daniel Merk 1,  Denys Pogoryelov 8,  Dieter Steinhilber 1,  Stefan Knapp 1 2,  Jeremy Bellien 3 9,  Ewgenij Proschak 1
Affiliations

Affiliations

  • 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.
PMID: 31436984 DOI: 10.1021/acs.jmedchem.9b00445
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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