4OD0

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

Summary for 4OD0

• Entry DOI: 10.2210/pdb4od0/pdb
• Related: 4OCZ
• Descriptor: Bifunctional epoxide hydrolase 2, PHOSPHATE ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: domain-swapped dimer, 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: 63164.24

Authors

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. (deposition date: 2014-01-09, release date: 2014-09-24, Last modification date: 2023-09-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.92 Å)