4JNC

Soluble Epoxide Hydrolase complexed with a carboxamide inhibitor

4JNC の概要

• エントリーDOI: 10.2210/pdb4jnc/pdb
• 分子名称: Bifunctional epoxide hydrolase 2, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N-[2-(trifluoromethyl)benzyl]piperidine-4-carboxamide (3 entities in total)
• 機能のキーワード: epoxide hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P34913
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36543.83

構造登録者

Shewchuk, L.M. (登録日: 2013-03-15, 公開日: 2013-06-05, 最終更新日: 2023-09-20)

主引用文献

Thalji, R.K.,McAtee, J.J.,Belyanskaya, S.,Brandt, M.,Brown, G.D.,Costell, M.H.,Ding, Y.,Dodson, J.W.,Eisennagel, S.H.,Fries, R.E.,Gross, J.W.,Harpel, M.R.,Holt, D.A.,Israel, D.I.,Jolivette, L.J.,Krosky, D.,Li, H.,Lu, Q.,Mandichak, T.,Roethke, T.,Schnackenberg, C.G.,Schwartz, B.,Shewchuk, L.M.,Xie, W.,Behm, D.J.,Douglas, S.A.,Shaw, A.L.,Marino, J.P.
Discovery of 1-(1,3,5-triazin-2-yl)piperidine-4-carboxamides as inhibitors of soluble epoxide hydrolase.
Bioorg.Med.Chem.Lett., 23:3584-3588, 2013

PubMed Abstract: 1-(1,3,5-Triazin-yl)piperidine-4-carboxamide inhibitors of soluble epoxide hydrolase were identified from high through-put screening using encoded library technology. The triazine heterocycle proved to be a critical functional group, essential for high potency and P450 selectivity. Phenyl group substitution was important for reducing clearance, and establishing good oral exposure. Based on this lead optimization work, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[[4-bromo-2-(trifluoromethoxy)]-phenyl]methyl}-4-piperidinecarboxamide (27) was identified as a useful tool compound for in vivo investigation. Robust effects on a serum biomarker, 9, 10-epoxyoctadec-12(Z)-enoic acid (the epoxide derived from linoleic acid) were observed, which provided evidence of robust in vivo target engagement and the suitability of 27 as a tool compound for study in various disease models.

PubMed: 23664879
DOI: 10.1016/j.bmcl.2013.04.019

実験手法

X-RAY DIFFRACTION (1.96 Å)