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Journal articles
Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain
Jan Kramer
1
Stefano Woltersdorf
1
Thomas Duflot
2, 3
Kerstin Hiesinger
1
Felix Lillich
1
Felix Knoll
1
Sandra Wittmann
1
Franca-M Klingler
1
Steffen Brunst
1
Apirat Chaikuad
1
Christophe Morisseau
4
Bruce Hammock
4
Carola Buccellati
5
Angelo Sala
5
Enrico Rovati
5
Matthieu Leuillier
2
Sylvain Fraineau
2
Julie Rondeaux
2
Victor Hernandez-Olmos
1, 6
Jan Heering
1, 6
Daniel Merk
1
Denys Pogoryelov
1
Dieter Steinhilber
1
Stefan Knapp
1, 3
Jeremy Bellien
2, 3
Ewgenij Proschak
1
Jan Kramer 1
Author
Stefano Woltersdorf 1
Author
Thomas Duflot 2, 3
Author
Kerstin Hiesinger 1
Author
Steffen Brunst 1
Author
Apirat Chaikuad 1
Author
Christophe Morisseau 4
Author
Bruce Hammock 4
Author
Carola Buccellati 5
Author
Angelo Sala 5
Author
Enrico G Rovati 5
Author
Matthieu Leuillier 2
Author
Sylvain Fraineau 2
Author
Julie Rondeaux 2
Author
Victor Hernandez-Olmos 1, 6
Author
Jan Heering 1, 6
Author
Jeremy Bellien 2, 3
Author
Ewgenij Proschak 1
Author
1
Goethe-University Frankfurt am Main (Theodor-W.-Adorno-Platz 1 , 60323 Frankfurt am Main - Germany)
2
EnVI - Endothélium, valvulopathies et insuffisance cardiaque (22 Boulevard Gambetta 76183 Rouen - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1096 (101, rue de Tolbiac, 75013 Paris - France)
- UNIROUEN - Université de Rouen Normandie : U1096 (1, rue Thomas Becket 76821 Mont-Saint-Aignan Cedex - France)
- NU - Normandie Université (Esplanade de la Paix - CS 14032 - 14032 Caen Cedex 5 - France)
3
CHU Rouen (1, rue de Germont 76031 Rouen cedex - France)
- NU - Normandie Université (Esplanade de la Paix - CS 14032 - 14032 Caen Cedex 5 - France)
4
UC Davis - University of California [Davis] (One Shields Avenue, , Davis, CA 95616-5294 - United States)
- University of California (United States)
5
Università degli studi di Milano [Milano] (Via Festa del Perdono 7 - 20122 Milano - Italy)
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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https://www.hal.inserm.fr/inserm-02444610
Contributor : Sylvain Fraineau <>
Submitted on : Saturday, January 18, 2020 - 11:08:19 AM
Last modification on : Thursday, January 23, 2020 - 1:30:55 AM
Contributor : Sylvain Fraineau <>
Submitted on : Saturday, January 18, 2020 - 11:08:19 AM
Last modification on : Thursday, January 23, 2020 - 1:30:55 AM
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Identifiers
- HAL Id : inserm-02444610, version 1
- DOI : 10.1021/acs.jmedchem.9b00445
- PUBMED : 31436984
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Citation
Jan Kramer, Stefano Woltersdorf, Thomas Duflot, Kerstin Hiesinger, Felix Lillich, et al.. Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain. Journal of Medicinal Chemistry, American Chemical Society, 2019, 62 (18), pp.8443-8460. ⟨10.1021/acs.jmedchem.9b00445⟩. ⟨inserm-02444610⟩
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