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
  • 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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