| Structural highlights
Function
[HYES_HUMAN] Bifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides. Also determines steady-state levels of physiological mediators. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid, 12-phosphonooxy-octadec-9E-enoic acid, and p-nitrophenyl phospate.[1] [2]
Publication Abstract from PubMed
Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The optimized lead structure displayed cellular activity in human polymorphonuclear leukocytes, oral bioavailability, and target engagement in vivo and demonstrated profound anti-inflammatory and anti-fibrotic efficiency in a kidney injury model caused by unilateral ureteral obstruction in mice. These results pave the way for investigating the therapeutic potential of dual 5-LOX/sEH inhibitors in other inflammation- and fibrosis-related disease models.
Design, Synthesis, and Structure-Activity Relationship Studies of Dual Inhibitors of Soluble Epoxide Hydrolase and 5-Lipoxygenase.,Hiesinger K, Kramer JS, Beyer S, Eckes T, Brunst S, Flauaus C, Wittmann SK, Weizel L, Kaiser A, Kretschmer SBM, George S, Angioni C, Heering J, Geisslinger G, Schubert-Zsilavecz M, Schmidtko A, Pogoryelov D, Pfeilschifter J, Hofmann B, Steinhilber D, Schwalm S, Proschak E J Med Chem. 2020 Oct 12. doi: 10.1021/acs.jmedchem.0c00561. PMID:33044073[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cronin A, Mowbray S, Durk H, Homburg S, Fleming I, Fisslthaler B, Oesch F, Arand M. The N-terminal domain of mammalian soluble epoxide hydrolase is a phosphatase. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1552-7. Epub 2003 Feb 6. PMID:12574508 doi:10.1073/pnas.0437829100
- ↑ Newman JW, Morisseau C, Harris TR, Hammock BD. The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1558-63. Epub 2003 Feb 6. PMID:12574510 doi:10.1073/pnas.0437724100
- ↑ Hiesinger K, Kramer JS, Beyer S, Eckes T, Brunst S, Flauaus C, Wittmann SK, Weizel L, Kaiser A, Kretschmer SBM, George S, Angioni C, Heering J, Geisslinger G, Schubert-Zsilavecz M, Schmidtko A, Pogoryelov D, Pfeilschifter J, Hofmann B, Steinhilber D, Schwalm S, Proschak E. Design, Synthesis, and Structure-Activity Relationship Studies of Dual Inhibitors of Soluble Epoxide Hydrolase and 5-Lipoxygenase. J Med Chem. 2020 Oct 12. doi: 10.1021/acs.jmedchem.0c00561. PMID:33044073 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c00561
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