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Discovery of first in vivo active inhibitors of soluble epoxide hydrolase (sEH) phosphatase domain

DOI: 10.1021/acs.jmedchem.9b00445 DOI Help

Authors: Jan S. Kramer (Goethe-University Frankfurt) , Stefano Woltersdorf (Goethe-University Frankfurt) , Thomas Duflot (Rouen University Hospital) , Kerstin Hiesinger (Goethe-University Frankfurt) , Felix F. Lillich (Goethe-University Frankfurt) , Felix Knöll (Goethe-University Frankfurt) , Sandra K. Wittmann (Goethe-University Frankfurt) , Franca M. Klingler (Goethe-University Frankfurt) , Steffen Brunst (Goethe-University Frankfurt) , Apirat Chaikuad (Goethe-University Frankfurt) , Christophe Morisseau (University of California Davis) , Bruce D. Hammock (University of California Davis) , Carola Buccellati (University of Milan) , Angelo Sala (University of Milan) , G. Enrico Rovati (University of Milan) , Matthieu Leuillier (Normandie Univ, UNIROUEN) , Sylvain Fraineau (Normandie Univ, UNIROUEN) , Julie Rondeaux (Normandie Univ, UNIROUEN) , Victor Hernandez Olmos (Goethe-University Frankfurt; Fraunhofer IME-TMP) , Jan Heering (Goethe-University Frankfurt; Fraunhofer IME-TMP) , Daniel Merk (Goethe-University Frankfurt) , Denys Pogoryelov (Goethe-University Frankfurt) , Dieter Steinhilber (Goethe-University Frankfurt) , Stefan Knapp (Goethe-University Frankfurt; Rouen University Hospital) , Jeremy Bellien (Normandie Univ, UNIROUEN; Rouen University Hospital) , Ewgenij Proschak (Goethe-University Frankfurt)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: August 2019

Abstract: The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities, which 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 domain of the sEH (sEH-P). Herein, we report the discovery and optimization of the first inhibitor of human and rat sEH-P, 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.

Journal Keywords: soluble epoxide hydrolase; phosphatase; oxazoles; crystal structure; chemical probe; lysophosphatidic acid

Diamond Keywords: Enzymes

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I02-Macromolecular Crystallography

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)