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Advancing Soluble Epoxide Hydrolase Inhibitors for the Treatment of Osteoarthritis in Companion Animals.
Author(s) -
McReynolds Cindy,
Hwang Sung Hee,
Yang Jun,
Wagner Karen,
Schmidt William K.,
Hammock Bruce
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.559.7
Subject(s) - osteoarthritis , epoxide hydrolase 2 , potency , medicine , analgesic , pharmacokinetics , pharmacology , arthritis , observational study , enzyme , chemistry , in vitro , biochemistry , pathology , alternative medicine
Soluble epoxide hydrolase inhibitors (sEHI) stabilize biologically active lipid metabolites responsible for regulating homeostatic biological processes. Over the past 20 years, researchers at the University of California at Davis synthesized a large chemical library of potent sEHIs to elucidate the role of this enzyme in biological systems. These chemical inhibitors helped identify analgesic effects of inhibiting the sEH enzyme. Further characterization of safety, enzyme potency and efficacy in mice, rats and dogs identified compound, EC1728, as a lead compound for translation into clinical development for the treatment of painful conditions, such as osteoarthritis. Data will be presented to provide an overview of the screening results that led to the selection of EC1728 for use in companion animals, as well as the results of the initial efficacy study in dogs. To assess efficacy, EC1728 was tested in a naturally occurring arthritis model. Aged beagles (8 per group) with naturally occurring arthritis confirmed by radiographic score were used in this study. Two additional animals were included in a satellite group to measure pharmacokinetic parameters. Dogs were treated once daily with an oral dose of sEHI for five days. Pain measurements were based on an observational questionnaire administered by a blinded clinician that assessed both pain and function. After five days, EC1728 significantly reduced cumulative pain at a dose of 5 mg/kg compared to vehicle controls. Pharmacokinetic evaluation showed concentrations exceeding the enzyme potency in both plasma and synovial fluid. These results provide proof of concept that EC1728 is efficacious in treating osteoarthritis in dogs. EC1728 is a non‐NSAID, non‐opioid compound targeting a novel mechanism of action. Considering these positive efficacy results and good safety profile, as well as the selective potency of inhibiting the sEH enzyme, EC1728 is being developed for use as a safer alternative for the treatment of osteoarthritis in companion animals. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .