6AUM

Crystal structure of human soluble epoxide hydrolase complexed with trans-4-[4-(3-trifluoromethoxyphenyl-l-ureido)-cyclohexyloxy]-benzoic acid.

6AUM の概要

• エントリーDOI: 10.2210/pdb6aum/pdb
• 分子名称: Bifunctional epoxide hydrolase 2, PHOSPHATE ION, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: soluble epoxide hydrolase, urea inhibitors, neuropathic pain, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 63349.65

構造登録者

Kodani, S.D.,Bahkta, S.,Hwang, S.H.,Pakhomova, S.,Newcomer, M.E.,Morisseau, C.,Hammock, B. (登録日: 2017-09-01, 公開日: 2018-02-07, 最終更新日: 2023-10-04)

主引用文献

Kodani, S.D.,Bhakta, S.,Hwang, S.H.,Pakhomova, S.,Newcomer, M.E.,Morisseau, C.,Hammock, B.D.
Identification and optimization of soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase.
Bioorg. Med. Chem. Lett., 28:762-768, 2018

PubMed Abstract: Multi-target inhibitors have become increasing popular as a means to leverage the advantages of poly-pharmacology while simplifying drug delivery. Here, we describe dual inhibitors for soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), two targets known to synergize when treating inflammatory and neuropathic pain. The structure activity relationship (SAR) study described herein initially started with t-TUCB (trans-4-[4-(3-trifluoromethoxyphenyl-l-ureido)-cyclohexyloxy]-benzoic acid), a potent sEH inhibitor that was previously shown to weakly inhibit FAAH. Inhibitors with a 6-fold increase of FAAH potency while maintaining high sEH potency were developed by optimization. Interestingly, compared to most FAAH inhibitors that inhibit through time-dependent covalent modification, t-TUCB and related compounds appear to inhibit FAAH through a time-independent, competitive mechanism. These inhibitors are selective for FAAH over other serine hydrolases. In addition, FAAH inhibition by t-TUCB appears to be higher in human FAAH over other species; however, the new dual sEH/FAAH inhibitors have improved cross-species potency. These dual inhibitors may be useful for future studies in understanding the therapeutic application of dual sEH/FAAH inhibition.

PubMed: 29366648
DOI: 10.1016/j.bmcl.2018.01.003

実験手法

X-RAY DIFFRACTION (2.95 Å)