4X6Y

Human soluble epoxide hydrolase in complex with a cyclopropyl urea derivative

Summary for 4X6Y

• Entry DOI: 10.2210/pdb4x6y/pdb
• Related: 4X6X
• Descriptor: Bifunctional epoxide hydrolase 2, 4-phenoxy-N-[(1S,2R)-2-phenylcyclopropyl]piperidine-1-carboxamide (3 entities in total)
• Functional Keywords: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 77965.70

Authors

Chiyo, N.,Takai, K.,Ishii, T. (deposition date: 2014-12-09, release date: 2015-04-08, Last modification date: 2023-11-08)

Primary citation

Takai, K.,Chiyo, N.,Nakajima, T.,Nariai, T.,Ishikawa, C.,Nakatani, S.,Ikeno, A.,Yamamoto, S.,Sone, T.
Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors.
Bioorg.Med.Chem.Lett., 25:1705-1708, 2015

PubMed Abstract: We have previously reported a series of cyclopropyl urea derivatives as potent orally available soluble epoxide hydrolase (sEH) inhibitors. Here, we designed and synthesized three substituted cyclopropane derivatives that occupy all available pockets of sEH catalytic domain. Compound 14 with a diphenyl substituted cyclopropyl moiety showed good sEH inhibitory activity. Co-crystal structure of this compound and human sEH hydrolase catalytic domain revealed enzyme pockets occupied by the phenoxypiperidine part and the diphenyl cyclopropyl moiety. Furthermore, investigation of the phenoxypiperidine part of compound 14 resulted in the discovery of compound 19, which showed potent sEH inhibitory activity (sub-nM sEH IC50 values).

PubMed: 25800114
DOI: 10.1016/j.bmcl.2015.02.076

Experimental method

X-RAY DIFFRACTION (2.1 Å)