Selection of Potent Inhibitors of Soluble Epoxide Hydrolase for Usage in Veterinary Medicine.

Autor: Shihadih DS; Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States., Harris TR; Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States., Kodani SD; Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States., Hwang SH; Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States., Lee KSS; Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States.; Department of Pharmacology and Toxicology and Department of Chemistry, Michigan State University, East Lansing, MI, United States., Mavangira V; Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, United States., Hamamoto B; Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States., Guedes A; Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN, United States., Hammock BD; Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States., Morisseau C; Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States.
Jazyk: angličtina
Zdroj: Frontiers in veterinary science [Front Vet Sci] 2020 Aug 26; Vol. 7, pp. 580. Date of Electronic Publication: 2020 Aug 26 (Print Publication: 2020).
DOI: 10.3389/fvets.2020.00580
Abstrakt: The veterinary pharmacopeia available to treat pain and inflammation is limited in number, target of action and efficacy. Inhibitors of soluble epoxide hydrolase (sEH) are a new class of anti-inflammatory, pro-resolving and analgesic drugs being tested in humans that have demonstrated efficacy in laboratory animals. They block the hydrolysis, and thus, increase endogenous concentrations of analgesic and anti-inflammatory signaling molecules called epoxy-fatty acids. Here, we screened a library of 2,300 inhibitors of the sEH human against partially purified feline, canine and equine hepatic sEH to identify inhibitors that are broadly potent among species. Six very potent sEH inhibitors (IC 50 < 1 nM 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 solvents suitable for the formulation of drugs. The trans -4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB, 1,728 ) appears to be the best compromise between stability and potency across species. Thus, it was selected for further testing in veterinary clinical trials of pain and inflammation in animals.
(Copyright © 2020 Shihadih, Harris, Kodani, Hwang, Lee, Mavangira, Hamamoto, Guedes, Hammock and Morisseau.)
Databáze: MEDLINE
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