4JNC

Soluble Epoxide Hydrolase complexed with a carboxamide inhibitor

Summary for 4JNC

• Entry DOI: 10.2210/pdb4jnc/pdb
• Descriptor: 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)
• Functional Keywords: epoxide hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P34913
• Total number of polymer chains: 1
• Total formula weight: 36543.83

Authors

Shewchuk, L.M. (deposition date: 2013-03-15, release date: 2013-06-05, Last modification date: 2023-09-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.96 Å)