4OD0

Crystal structure of human soluble epoxide hydrolase complexed with 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea

4OD0 の概要

• エントリーDOI: 10.2210/pdb4od0/pdb
• 関連するPDBエントリー: 4OCZ
• 分子名称: Bifunctional epoxide hydrolase 2, PHOSPHATE ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: domain-swapped dimer, 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: 63164.24

構造登録者

Lee, K.S.S.,Liu, J.,Wagner, K.M.,Pakhomova, S.,Dong, H.,Morisseau, C.,Fu, S.H.,Yang, J.,Wang, P.,Ulu, A.,Mate, C.,Nguyen, L.,Wullf, H.,Eldin, M.L.,Mara, A.A.,Newcomer, M.E.,Zeldin, D.C.,Hammock, B.D. (登録日: 2014-01-09, 公開日: 2014-09-24, 最終更新日: 2023-09-20)

主引用文献

Lee, K.S.,Liu, J.Y.,Wagner, K.M.,Pakhomova, S.,Dong, H.,Morisseau, C.,Fu, S.H.,Yang, J.,Wang, P.,Ulu, A.,Mate, C.A.,Nguyen, L.V.,Hwang, S.H.,Edin, M.L.,Mara, A.A.,Wulff, H.,Newcomer, M.E.,Zeldin, D.C.,Hammock, B.D.
Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy.
J.Med.Chem., 57:7016-7030, 2014

PubMed Abstract: Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.

PubMed: 25079952
DOI: 10.1021/jm500694p

実験手法

X-RAY DIFFRACTION (2.92 Å)