FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Front Vet Sci / Selection of Potent Inhibitors of Soluble Epoxide Hydrolase ...
Frontiers in veterinary science2020; 7; 580; doi: 10.3389/fvets.2020.00580

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

Abstract: 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 < 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 -4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB, ) 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.
Get Full Text
Publication Date: 2020-08-26 PubMed ID: 33005645PubMed Central: PMC7479175DOI: 10.3389/fvets.2020.00580Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research explored the selection of highly efficient inhibitors of soluble epoxide hydrolase (sEH) for use in veterinary medicine to manage pain and inflammation. The identified inhibitor, named t-TUCB, shows high potency in various animal species and will be further tested in clinical trials.

Research Objective and Context

  • The researchers focused on finding potent inhibitors of soluble epoxide hydrolase (sEH), a new class of drugs with anti-inflammatory, pro-resolving, and analgesic properties. These inhibitors have shown efficacy in lab animals and are being tested in humans.
  • As options for pain and inflammation treatment in veterinary medicine have limitations, the main objective was to broaden the available choices for veterinarians.
  • Other drugs, such as sEH inhibitors, could help improve the quality of veterinary care by offering more efficient solutions for pain and inflammation management.

Methodology

  • The team screened a library of 2,300 inhibitors of the human sEH enzyme, focusing on feline, canine, and equine hepatic sEH to find inhibitors effective in multiple species.
  • They then evaluated the microsomal stability of six highly potent inhibitors in hepatic extracts taken from cats, dogs, and horses.
  • Additionally, they assessed the solubility of these substances in solvents suitable for drug formulation.

Results and Conclusion

  • Six potent sEH inhibitors were identified, the potency of which was less than 1nM (nanomolar, a concentration measurement) for each enzyme tested.
  • The best balance between stability and efficacy across species was found in the t-TUCB (-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid) inhibitor.
  • This promising inhibitor will undergo further testing in veterinary clinical trials focused on pain and inflammation treatment in animals.

Implication

  • This research opens up new possibilities in veterinary medicine for therapeutic options to manage pain and inflammation, a common issue in animals.
  • It highlights the utility of studying inhibitors as alternative medicinal solutions in the veterinary field, which could enhance the well-being of animals worldwide.
  • Successful future trials of t-TUCB could significantly widen the range of pain and inflammation treatments available to veterinarians.

Cite This Article

APA
Shihadih DS, Harris TR, Kodani SD, Hwang SH, Lee KSS, Mavangira V, Hamamoto B, Guedes A, Hammock BD, Morisseau C. (2020). Selection of Potent Inhibitors of Soluble Epoxide Hydrolase for Usage in Veterinary Medicine. Front Vet Sci, 7, 580. https://doi.org/10.3389/fvets.2020.00580

Publication

Frontiers in veterinary science
ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 7
Pages: 580
PII: 580

Researcher Affiliations

Shihadih, Diyala S
  • Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States.
Harris, Todd R
  • Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States.
Kodani, Sean D
  • Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States.
Hwang, Sung-Hee
  • Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States.
Lee, Kin Sing Stephen
  • 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, Vengai
  • Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, United States.
Hamamoto, Briana
  • Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
Guedes, Alonso
  • 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, Bruce D
  • Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States.
Morisseau, Christophe
  • Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States.

Grant Funding

  • P42 ES004699 / NIEHS NIH HHS
  • R35 ES030443 / NIEHS NIH HHS
  • T32 GM099608 / NIGMS NIH HHS

References

This article includes 33 references
  1. Epstein M, Rodan I, Griffenhagen G, Kadrlik J, Petty M, Robertson S, Simpson W. 2015 AAHA/AAFP Pain Management Guidelines for Dogs and Cats.. J Am Anim Hosp Assoc 2015 Mar-Apr;51(2):67-84.
    doi: 10.5326/JAAHA-MS-7331pubmed: 25764070google scholar: lookup
  2. Cooper C, Chapurlat R, Al-Daghri N, Herrero-Beaumont G, Bruyère O, Rannou F, Roth R, Uebelhart D, Reginster JY. Safety of Oral Non-Selective Non-Steroidal Anti-Inflammatory Drugs in Osteoarthritis: What Does the Literature Say?. Drugs Aging 2019 Apr;36(Suppl 1):15-24.
    doi: 10.1007/s40266-019-00660-1pmc: PMC6509083pubmed: 31073921google scholar: lookup
  3. Driessen B, Bauquier SH, Zarucco L. Neuropathic pain management in chronic laminitis.. Vet Clin North Am Equine Pract 2010 Aug;26(2):315-37.
    doi: 10.1016/j.cveq.2010.04.002pubmed: 20699178google scholar: lookup
  4. McLean MK, Khan SA. Toxicology of Frequently Encountered Nonsteroidal Anti-inflammatory Drugs in Dogs and Cats: An Update.. Vet Clin North Am Small Anim Pract 2018 Nov;48(6):969-984.
    doi: 10.1016/j.cvsm.2018.06.003pubmed: 30149968google scholar: lookup
  5. Bergh MS, Budsberg SC. The coxib NSAIDs: potential clinical and pharmacologic importance in veterinary medicine.. J Vet Intern Med 2005 Sep-Oct;19(5):633-43.
    doi: 10.1892/0891-6640(2005)19[633:tcnpca]2.0.co;2pubmed: 16231707google scholar: lookup
  6. Sala A, Proschak E, Steinhilber D, Rovati GE. Two-pronged approach to anti-inflammatory therapy through the modulation of the arachidonic acid cascade.. Biochem Pharmacol 2018 Dec;158:161-173.
    doi: 10.1016/j.bcp.2018.10.007pubmed: 30315753google scholar: lookup
  7. Wagner K, Vito S, Inceoglu B, Hammock BD. The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling.. Prostaglandins Other Lipid Mediat 2014 Oct;113-115:2-12.
    doi: 10.1016/j.prostaglandins.2014.09.001pmc: PMC4254344pubmed: 25240260google scholar: lookup
  8. Kodani SD, Morisseau C. Role of epoxy-fatty acids and epoxide hydrolases in the pathology of neuro-inflammation.. Biochimie 2019 Apr;159:59-65.
    doi: 10.1016/j.biochi.2019.01.020pmc: PMC6431267pubmed: 30716359google scholar: lookup
  9. Wagner KM, McReynolds CB, Schmidt WK, Hammock BD. Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases.. Pharmacol Ther 2017 Dec;180:62-76.
    doi: 10.1016/j.pharmthera.2017.06.006pmc: PMC5677555pubmed: 28642117google scholar: lookup
  10. Morisseau C, Hammock BD. Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health.. Annu Rev Pharmacol Toxicol 2013;53:37-58.
    doi: 10.1146/annurev-pharmtox-011112-140244pmc: PMC3578707pubmed: 23020295google scholar: lookup
  11. Guedes AG, Morisseau C, Sole A, Soares JH, Ulu A, Dong H, Hammock BD. Use of a soluble epoxide hydrolase inhibitor as an adjunctive analgesic in a horse with laminitis.. Vet Anaesth Analg 2013 Jul;40(4):440-8.
    doi: 10.1111/vaa.12030pmc: PMC3956586pubmed: 23463912google scholar: lookup
  12. Guedes A, Galuppo L, Hood D, Hwang SH, Morisseau C, Hammock BD. Soluble epoxide hydrolase activity and pharmacologic inhibition in horses with chronic severe laminitis.. Equine Vet J 2017 May;49(3):345-351.
    doi: 10.1111/evj.12603pmc: PMC5580818pubmed: 27338788google scholar: lookup
  13. Guedes AGP, Aristizabal F, Sole A, Adedeji A, Brosnan R, Knych H, Yang J, Hwang SH, Morisseau C, Hammock BD. Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t-TUCB in horses with experimentally induced radiocarpal synovitis.. J Vet Pharmacol Ther 2018 Apr;41(2):230-238.
    doi: 10.1111/jvp.12463pmc: PMC5920688pubmed: 29067696google scholar: lookup
  14. McReynolds CB, Hwang SH, Yang J, Wan D, Wagner K, Morisseau C, Li D, Schmidt WK, Hammock BD. Pharmaceutical Effects of Inhibiting the Soluble Epoxide Hydrolase in Canine Osteoarthritis.. Front Pharmacol 2019;10:533.
    doi: 10.3389/fphar.2019.00533pmc: PMC6554663pubmed: 31214021google scholar: lookup
  15. Tsai HJ, Hwang SH, Morisseau C, Yang J, Jones PD, Kasagami T, Kim IH, Hammock BD. Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs.. Eur J Pharm Sci 2010 Jun 14;40(3):222-38.
    doi: 10.1016/j.ejps.2010.03.018pmc: PMC3285443pubmed: 20359531google scholar: lookup
  16. Jones PD, Wolf NM, Morisseau C, Whetstone P, Hock B, Hammock BD. Fluorescent substrates for soluble epoxide hydrolase and application to inhibition studies.. Anal Biochem 2005 Aug 1;343(1):66-75.
    doi: 10.1016/j.ab.2005.03.041pmc: PMC1447601pubmed: 15963942google scholar: lookup
  17. Hwang SH, Tsai HJ, Liu JY, Morisseau C, Hammock BD. Orally bioavailable potent soluble epoxide hydrolase inhibitors.. J Med Chem 2007 Aug 9;50(16):3825-40.
    doi: 10.1021/jm070270tpmc: PMC2596069pubmed: 17616115google scholar: lookup
  18. Shihadih DS, Harris TR, Yang J, Merzlikin O, Lee KS, Hammock BD, Morisseau C. Identification of potent inhibitors of the chicken soluble epoxide hydrolase.. Bioorg Med Chem Lett 2015 Jan 15;25(2):276-9.
    doi: 10.1016/j.bmcl.2014.11.053pmc: PMC4277729pubmed: 25479771google scholar: lookup
  19. Crow JA, Bittles V, Herring KL, Borazjani A, Potter PM, Ross MK. Inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by chlorpyrifos oxon, paraoxon and methyl paraoxon.. Toxicol Appl Pharmacol 2012 Jan 1;258(1):145-50.
    doi: 10.1016/j.taap.2011.10.017pmc: PMC3345137pubmed: 22100607google scholar: lookup
  20. Morisseau C, Hammock BD. Measurement of soluble epoxide hydrolase (sEH) activity.. Curr Protoc Toxicol 2007;Chapter 4:Unit 4.23.
    doi: 10.1002/0471140856.tx0423s33pubmed: 23045145google scholar: lookup
  21. Shan G, Hammock BD. Development of sensitive esterase assays based on alpha-cyano-containing esters.. Anal Biochem 2001 Dec 1;299(1):54-62.
    doi: 10.1006/abio.2001.5388pubmed: 11726184google scholar: lookup
  22. Wolf NM, Morisseau C, Jones PD, Hock B, Hammock BD. Development of a high-throughput screen for soluble epoxide hydrolase inhibition.. Anal Biochem 2006 Aug 1;355(1):71-80.
    doi: 10.1016/j.ab.2006.04.045pmc: PMC1964503pubmed: 16729954google scholar: lookup
  23. Zhang JH, Chung TD, Oldenburg KR. A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays.. J Biomol Screen 1999;4(2):67-73.
    doi: 10.1177/108705719900400206pubmed: 10838414google scholar: lookup
  24. Pecic S, Zeki AA, Xu X, Jin GY, Zhang S, Kodani S, Halim M, Morisseau C, Hammock BD, Deng SX. Novel piperidine-derived amide sEH inhibitors as mediators of lipid metabolism with improved stability.. Prostaglandins Other Lipid Mediat 2018 May;136:90-95.
    doi: 10.1016/j.prostaglandins.2018.02.004pmc: PMC5970965pubmed: 29567338google scholar: lookup
  25. Newman JW, Morisseau C, Hammock BD. Epoxide hydrolases: their roles and interactions with lipid metabolism.. Prog Lipid Res 2005 Jan;44(1):1-51.
    doi: 10.1016/j.plipres.2004.10.001pubmed: 15748653google scholar: lookup
  26. Liu JY, Lin YP, Qiu H, Morisseau C, Rose TE, Hwang SH, Chiamvimonvat N, Hammock BD. Substituted phenyl groups improve the pharmacokinetic profile and anti-inflammatory effect of urea-based soluble epoxide hydrolase inhibitors in murine models.. Eur J Pharm Sci 2013 Mar 12;48(4-5):619-27.
    doi: 10.1016/j.ejps.2012.12.013pmc: PMC3596469pubmed: 23291046google scholar: lookup
  27. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.. Adv Drug Deliv Rev 2001 Mar 1;46(1-3):3-26.
    doi: 10.1016/s0169-409x(00)00129-0pubmed: 11259830google scholar: lookup
  28. Burmistrov V, Morisseau C, Lee KS, Shihadih DS, Harris TR, Butov GM, Hammock BD. Symmetric adamantyl-diureas as soluble epoxide hydrolase inhibitors.. Bioorg Med Chem Lett 2014 May 1;24(9):2193-7.
    doi: 10.1016/j.bmcl.2014.03.016pmc: PMC4019751pubmed: 24685540google scholar: lookup
  29. Biernacki M, Skrzydlewska E. Metabolism of endocannabinoids.. Postepy Hig Med Dosw (Online) 2016 Aug 11;70(0):830-43.
    doi: 10.5604/17322693.1213898pubmed: 27516570google scholar: lookup
  30. Di L. The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics.. Curr Drug Metab 2019;20(2):91-102.
    doi: 10.2174/1389200219666180821094502pmc: PMC6635651pubmed: 30129408google scholar: lookup
  31. Liu R. Water-Insoluble Drug Formulation. 3rd Edition. Boca Raton, FL: CRC Press; (2018).
  32. Trevisi E, Zecconi A, Cogrossi S, Razzuoli E, Grossi P, Amadori M. Strategies for reduced antibiotic usage in dairy cattle farms.. Res Vet Sci 2014 Apr;96(2):229-33.
    doi: 10.1016/j.rvsc.2014.01.001pubmed: 24508188google scholar: lookup
  33. Mavangira V, Gandy JC, Zhang C, Ryman VE, Daniel Jones A, Sordillo LM. Polyunsaturated fatty acids influence differential biosynthesis of oxylipids and other lipid mediators during bovine coliform mastitis.. J Dairy Sci 2015 Sep;98(9):6202-15.
    doi: 10.3168/jds.2015-9570pubmed: 26162796google scholar: lookup

Citations

This article has been cited 6 times.
  1. Wagner KM, Yang J, Morisseau C, Hammock BD. Soluble Epoxide Hydrolase Deletion Limits High-Fat Diet-Induced Inflammation. Front Pharmacol 2021;12:778470.
    doi: 10.3389/fphar.2021.778470pubmed: 34975481google scholar: lookup
  2. McReynolds CB, Yang J, Guedes A, Morisseau C, Garcia R, Knych H, Tearney C, Hamamoto B, Hwang SH, Wagner K, Hammock BD. Species Differences in Metabolism of Soluble Epoxide Hydrolase Inhibitor, EC1728, Highlight the Importance of Clinically Relevant Screening Mechanisms in Drug Development. Molecules 2021 Aug 19;26(16).
    doi: 10.3390/molecules26165034pubmed: 34443621google scholar: lookup
  3. Larsson N, McReynolds CB, Hwang SH, Wan D, Yang J, Lindberg R, Lehtipalo S, Claesson J, Liljeström AI, Lind A, Brolin A, Mettävainio MI, Hammock BD, Morisseau C, Nording ML. Inhibition of soluble epoxide hydrolase in endotoxin induced pig lung injury. Front Pharmacol 2025;16:1652349.
    doi: 10.3389/fphar.2025.1652349pubmed: 41001346google scholar: lookup
  4. Babkov D, Eliseeva N, Adzhienko K, Bagmetova V, Danilov D, McReynolds CB, Morisseau C, Hammock BD, Burmistrov V. Preclinical Evaluation of Soluble Epoxide Hydrolase Inhibitor AMHDU against Neuropathic Pain. Int J Mol Sci 2024 Aug 14;25(16).
    doi: 10.3390/ijms25168841pubmed: 39201526google scholar: lookup
  5. Hryckowian ND, Ramírez-Flores CJ, Zinda C, Park SC, Kelty MT, Knoll LJ. Host cell-specific metabolism of linoleic acid controls Toxoplasma gondii growth in cell culture. Infect Immun 2024 Oct 15;92(10):e0029924.
    doi: 10.1128/iai.00299-24pubmed: 39194219google scholar: lookup
  6. Hryckowian ND, Zinda C, Park SC, Kelty MT, Knoll LJ. Host cell-specific metabolism of linoleic acid controls Toxoplasma gondii growth in cell culture. bioRxiv 2024 Mar 25;.
    doi: 10.1101/2024.03.22.586332pubmed: 38562845google scholar: lookup
Subscribe to our newsletter
Join 99,030 horse owners like you who receive our email updates on horse health and nutrition.