UC Davis

There is currently an urgent need for safe and effective treatment options for chronic diseases, especially pain, given that current medicines are accompanied by severe side effects. Bioactive lipid mediators resulting from the metabolism of polyunsaturated fatty acids (PUFA) are controlled by many pathways that maintain homeostasis and prevent disease, and regulation of this pathway presents a novel and safe approach for treating many diseases, including pain. Epoxygenated fatty acids (EpFA), formed through metabolism by cytochrome P450 enzymes, are regulatory lipids that demonstrate largely anti-inflammatory properties that reduce endoplasmic reticulum stress to help resolve disease; however, their utility is limited by rapid degradation by the soluble epoxide hydrolase (sEH) into corresponding vicinal diols. Inhibiting its activity increases concentrations of beneficial EpFA, and often disease states correlate to increased sEH activity that results in decreased concentrations of EpFA in the body. Research described in this dissertation detail the pharmacological properties of EC1728, a novel soluble epoxide hydrolase inhibitor (sEHI), as an option for pain control in companion animals. The exposure and distribution are described in target animal species and demonstrate that there are differences in exposures between species that need to be considered for drug development. An efficacy study demonstrating pain relief after treatment with EC1728 in dogs with naturally occurring arthritis is also presented. Fundamentally, inhibition of the sEH is thought to offer therapeutic advantages by increasing EpFA; however, the last chapter explores lipidomics profiles in patients with severe COVID-19 disease to advance the idea that metabolism products of EpFA, specifically the diols resulting from linoleic acid metabolism, are also responsible for driving severe inflammatory disease. These studies demonstrate that sEH inhibition is beneficial by both increasing EpFA and decreasing inflammatory diol metabolites. In summary, pharmacological properties of EC1728 demonstrate suitable properties for developing as a pain-relieving therapy in companion animals, and also validation of sEHI as a therapeutic target by demonstrating inhibition in natural disease in addition to laboratory models. The methods described here of characterizing detailed drug exposure, characterizing efficacy in companion animals with natural disease, as well as identification of biomarkers in disease settings represents a novel approach to drug discovery that may help advance selection of safe and effective treatments for multimodal diseases.