6FR2

Soluble epoxide hydrolase in complex with LK864

6FR2 の概要

• エントリーDOI: 10.2210/pdb6fr2/pdb
• 分子名称: 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)
• 機能のキーワード: inhibitor, complex, seh, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40166.38

構造登録者

Kramer, J.S.,Pogoryelov, D.,Krasavin, M.,Proschak, E. (登録日: 2018-02-15, 公開日: 2018-09-12, 最終更新日: 2024-01-17)

主引用文献

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

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: 30059891
DOI: 10.1016/j.bioorg.2018.07.014

実験手法

X-RAY DIFFRACTION (2.262 Å)