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Novel inhibitors of the soluble epoxide hydrolase block pain in multiple models
Author(s) -
Wagner Karen,
Lee Kin Sing Stephen,
Hwang Sung Hee,
Hammock Bruce D.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.927.7
Subject(s) - epoxide hydrolase 2 , chemistry , pharmacology , arachidonic acid , docosahexaenoic acid , cytochrome p450 , neuropathic pain , biochemistry , enzyme , fatty acid , medicine , polyunsaturated fatty acid
The soluble epoxide hydrolase (sEH) is a master regulatory enzyme downstream in the cytochrome P450 (CYP450) branch of the arachidonic acid (ARA) cascade. The sEH enzyme is the principal route of degradation for the bioactive epoxidized metabolites of long chain fatty acids formed by CYP450 activity. The most studied of these are the epoxyeicosatrienoic acids (EETs) but the epoxidized metabolites of both docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) the epoxydocosapentanoic acids (EDPs) and eicosatetraenoic acids (EEQs) respectively are known substrates of sEH. Targeting the sEH to inhibit the metabolism of these epoxy fatty acids (EpFAs) has been shown to be antiinflammatory, antihypertensive and to delay seizure. Important to the focus of this work, inhibiting sEH has also been efficacious against both inflammatory and neuropathic pain. Here we use newly designed inhibitors based on a N, N′ disubstituted urea pharmacophore guided by crystal structures which have exhibited improved drug‐like properties, pharmacokinetic profiles and potency in both equilibrium binding and drug residence time on the recombinant sEH of several species. This increased potency and druggability has transferred into better efficacy against modeled pain in vivo . We have tested the efficacy of these inhibitors in models of murine inflammatory pain and induced diabetic neuropathic pain. Newly we have extended this testing to the Akita mouse model which has a genetic mutation in the insulin receptor resulting in a loss of function and eventual type I diabetes. The inhibitors were potent and efficacious in these models using both withdrawal and operant nociceptive assays. Additionally, the inhibitors show synergy with both coxibs and fatty acid amide hydrolase inhibitors and the absence of any reward side effects which relate with addiction potential as seen with narcotics. Thus, targeting sEH is a promising strategy to alleviate pain and holds potential for impacting human health with translation to the clinic. Support or Funding Information NIEHS R01 ES002710, NIEHS/Superfund P42 ES004699, NIH/NIDDK U24 DK097154, NIDDK R01DK090492, KW is supported by 5 T32L086350‐08.