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.

Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain / J.S. Kramer, S. Woltersdorf, T. Duflot, K. Hiesinger, F.F. Lillich, F. Knöll, S.K. Wittmann, F. Klingler, S. Brunst, A. Chaikuad, C. Morisseau, B.D. Hammock, C. Buccellati, A. Sala, G. Rovati, M. Leuillier, S. Fraineau, J. Rondeaux, V. Hernandez-Olmos, J. Heering, D. Merk, D. Pogoryelov, D. Steinhilber, S. Knapp, J. Bellien, E. Proschak. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 62:18(2019 Sep 26), pp. 8443-8460.

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

C. Buccellati;A. Sala;G. Rovati;
2019

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.
Settore BIO/14 - Farmacologia
26-set-2019
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/678668
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