6fr2

Soluble epoxide hydrolase in complex with LK864

spinqualitylabelsall models 6fr2, resolution 2.26Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6fr2 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: E3N, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. Publication Abstract from PubMed Spirocyclic 1-oxa-9-azaspiro[5.5]undecan-4-amine scaffold was explored as a basis for the design of potential inhibitors of soluble epoxide hydrolase (sEH). Synthesis and testing of the initial SAR-probing library followed by biochemical testing against sEH allowed nominating a racemic lead compound (+/-)-22. The latter showed remarkable (> 0.5mM) solubility in aqueous phosphate buffer solution, unusually low (for sEH inhibitors) lipophilicity as confirmed by experimentally determined logD7.4 of 0.99, and an excellent oral bioavailability in mice (as well as other pharmacokinetic characteristics). Individual enantiomer profiling revealed that the inhibitory potency primarily resided with the dextrorotatory eutomer (+)-22 (IC50 4.99+/-0.18nM). For the latter, a crystal structure of its complex with a C-terminal domain of sEH was obtained and resolved. These data fully validate (+)-22 as a new non-racemic advanced lead compound for further development as a potential therapeutic agent for use in such areas as cardiovascular disease, inflammation and pain. Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase.,Lukin A, Kramer J, Hartmann M, Weizel L, Hernandez-Olmos V, Falahati K, Burghardt I, Kalinchenkova N, Bagnyukova D, Zhurilo N, Rautio J, Forsberg M, Ihalainen J, Auriola S, Leppanen J, Konstantinov I, Pogoryelov D, Proschak E, Dar'in D, Krasavin M Bioorg Chem. 2018 Oct;80:655-667. doi: 10.1016/j.bioorg.2018.07.014. Epub 2018, Jul 17. PMID:30059891 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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