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Inhibitors of soluble epoxide hydrolase (sEH) enzymes have shown great potential for the treatment of neuropathic pain. However, current sEH inhibitors have poor physicochemical properties and has not been proven to be safe for human treatments yet. New inhibitor designs could have the potential to improve current drugs’ efficacy, and so in this work, chemical intuition and bioisosteric replacement were used to computationally design two novel sEH inhibitors. These new candidates showed good pharmacokinetic properties and presented better docking scores compared to a known sEH inhibitor, t-TUCB, used in the treatment of pain in horses. Homology analysis revealed that Mus musculus may not be suitable organism for preclinical trials studies of these novel inhibitors.