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

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 phos...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2019-09, Vol.62 (18), p.8443-8460
Main Authors: 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, Proschak, Ewgenij
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Biotechnology
Catalytic Domain
Drug Design
Enzyme Inhibitors - chemistry
Epoxide Hydrolases - antagonists & inhibitors
Epoxide Hydrolases - chemistry
Humans
Life Sciences
Ligands
Male
Oxazoles - chemistry
Phosphoric Monoester Hydrolases - chemistry
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Temperature
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b00445