Selection of Potent Inhibitors of Soluble Epoxide Hydrolase for Usage in Veterinary Medicine.
Authors: Shihadih Diyala S, Harris Todd R, Kodani Sean D, Hwang Sung-Hee, Lee Kin Sing Stephen, Mavangira Vengai, Hamamoto Briana, Guedes Alonso, Hammock Bruce D, Morisseau Christophe
Journal: Frontiers in veterinary science
Summary
# Editorial Summary Soluble epoxide hydrolase (sEH) inhibitors represent a promising therapeutic avenue for managing pain and inflammation in veterinary medicine, operating through a distinct mechanism—they preserve endogenous epoxy-fatty acids that possess inherent analgesic and anti-inflammatory properties—offering potential advantages over conventional non-steroidal anti-inflammatories that many equine practitioners currently rely upon. Diyala and colleagues screened 2,300 human sEH inhibitors against partially purified hepatic enzymes from cats, dogs and horses to identify compounds with broad-spectrum potency, ultimately identifying six inhibitors with IC₅₀ values below 1 nanomolar across all three species. Following this screening, the researchers evaluated microsomal stability of lead candidates in hepatic extracts from all three species alongside their solubility profiles suitable for pharmaceutical formulation, determining that t-TUCB (compound 1,728) offered the optimal balance between metabolic stability and potency across feline, canine and equine models. For equine practitioners, this work suggests a new analgesic and anti-inflammatory option may soon enter clinical trials, potentially expanding the limited pharmacological toolkit currently available for managing pain—particularly valuable given increasing concerns about prolonged NSAID administration and the variable efficacy of existing alternatives. The cross-species validation methodology employed here strengthens confidence that compounds selected will translate effectively to clinical application in horses, though results from forthcoming veterinary clinical trials will ultimately determine whether sEH inhibition offers meaningful advantages in real-world equine pain management scenarios.
Read the full abstract on PubMed
Practical Takeaways
- •sEH inhibitors represent a novel pharmacological approach to pain and inflammation management that may expand limited veterinary analgesic options
- •t-TUCB shows promise as a potential new therapeutic agent, but clinical efficacy and safety in horses remain to be determined in ongoing trials
- •This drug class works through a different mechanism (pro-resolution and endogenous signaling) than conventional NSAIDs, potentially offering an alternative for cases with limited NSAID tolerance
Key Findings
- •Six sEH inhibitors demonstrated potency (IC50 < 1 nM) across feline, canine and equine hepatic enzymes
- •t-TUCB (1,728) showed optimal balance between enzymatic stability and potency across all three species tested
- •sEH inhibitors increase endogenous epoxy-fatty acids with analgesic and anti-inflammatory properties
- •t-TUCB selected as lead compound for advancement to veterinary clinical trials