6FR2
Soluble epoxide hydrolase in complex with LK864
Summary for 6FR2
| Entry DOI | 10.2210/pdb6fr2/pdb |
| Descriptor | Bifunctional epoxide hydrolase 2, 1-[(4~{S})-9-propan-2-ylsulfonyl-1-oxa-9-azaspiro[5.5]undecan-4-yl]-3-[[4-(trifluoromethyloxy)phenyl]methyl]urea, MAGNESIUM ION, ... (4 entities in total) |
| Functional Keywords | inhibitor, complex, seh, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 40166.38 |
| Authors | Kramer, J.S.,Pogoryelov, D.,Krasavin, M.,Proschak, E. (deposition date: 2018-02-15, release date: 2018-09-12, Last modification date: 2024-01-17) |
| Primary citation | 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. Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase. Bioorg. Chem., 80:655-667, 2018 Cited by PubMed Abstract: 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 (> 0.5 mM) solubility in aqueous phosphate buffer solution, unusually low (for sEH inhibitors) lipophilicity as confirmed by experimentally determined logD 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 (IC 4.99 ± 0.18 nM). 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. PubMed: 30059891DOI: 10.1016/j.bioorg.2018.07.014 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.262 Å) |
Structure validation
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