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Identification of Potent Soluble Epoxide Hydrolase Inhibitors for Veterinarian Usage
Author(s) -
Morisseau Christophe,
Shihadih Diyala S.,
Harris Todd R.,
Kodani Sean D.,
Hwang SungHee,
Lee Kin Sing S.,
Hamamoto Briana,
Guedes Alonso,
Hammock Bruce D.
Publication year - 2018
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.2018.32.1_supplement.559.5
Subject(s) - epoxide hydrolase 2 , pharmacology , in vivo , chemistry , inflammation , analgesic , ibuprofen , cats , epoxide hydrolase , cyclooxygenase , nociception , anti inflammatory , enzyme , medicine , receptor , biochemistry , microsome , biology , immunology , microbiology and biotechnology
The veterinary pharmacopeia to treat pain and inflammation in companion animals is very limited. Currently, cyclooxygenase inhibitors (both NSAIDs and COXIBs) are the main class of drugs available to reduce pain and inflammation in cats, dogs and horses. However, these drugs often have insufficient efficacy and a great number of known adverse effects, underlying the need for novel pain medication for companion animals. Soluble epoxide hydrolase (sEH) inhibitors are a new class of anti‐inflammatory and analgesic drugs being tested in humans. They block the hydrolysis, and thus increase endogenous concentrations, of signaling molecules called epoxy‐fatty acids (EpFAs) that modulate inflammation and nociception. In addition to their use in human, sEH inhibitors may be a suitable alternative to cyclooxygenase inhibitors in companion animals. However, the compounds optimized for usage in primates and rodents are typically not sufficiently potent inhibitors of other animals' sEH for in vivo usage. Here, we screened a library of 2,300 inhibitors developed for the human enzyme with partially purified feline, canine and equine hepatic sEH to identify inhibitors that are broadly potent among species. Six candidate sEH inhibitors that are very potent across species (IC 50 < 1nM for each enzyme tested) were identified. Their microsomal stability was then measured in hepatic extracts from cat, dog and horse, as well as their solubility in drug‐able solvents. Based on this work, trans ‐4‐{4‐[3‐(4‐trifluoromethoxy‐phenyl)‐ureido]‐cyclohexyloxy}‐benzoic acid was selected for further testing in veterinary clinical trials of pain and inflammation in companion animals. Support or Funding Information This work was supported by the National Institute of Environmental Health Sciences grant numbers ES002710 and ES004699. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .