The soluble epoxide hydrolase (sEH) is an alpha/beta hydrolase fold enzyme that rapidly converts epoxyfatty acids (EpFAs) to the corresponding diols. EpFAs are lipid mediators which resolve inflammation including neuroinflammation, block pathological fibrosis, reduce hypertension and ameliorate both inflammatory and neuropathic pain. sEH inhibitors (sEHI) stabilize EpFAs thus increasing their biological lives and potency. sEHI act in a variety of disease states to increase mitochondrial stability and reduce endoplasmic reticulum stress. Target occupancy was found to be the best <i>in vitro</i> predictor of <i>in vivo</i> efficacy for the sEHI, and the clinical candidate is a transition state mimic with slow off rate. The analgesic potency of the class has been shown in a number of rodent models as well as in equine and other veterinary patients. Operant tests fail to indicate addiction potential and in fact suggest a reduction in opioid withdraw hyperalgesia (pain). sEHI synergize with NSAIDs and COXIBs. sEHI do not show the gastrointestinal side effects of COXIBs and NSAIDs and reverse GI erosion in animal models. The previously described sEH inhibitor TPPU is a commonly used tool compound with a low Ki and good in vivo target occupancy, excellent oral bioavailability and good pharmacokinetics. TPPU shows strong activity in a number of human pluripotent stem cell and murine models of CNS disorders including Alzheimer’s, autism, depression, Lewy body dementia, schizophrenia and others. The sEH protein and message are increased in key regions of the brain and EpFAs are altered as expected in both murine models and human cadaveric samples with CNS inflammation suggesting broad application to CNS disorders. The novel clinical candidate sEHI, EicOsis 5026, has low picomolar potency on the human recombinant sEH, good oral availability and excellent PK-ADME. It has completed initial CMC and IND enabling work showing a good safety profile and an excellent therapeutic index. This peripherally restricted compound is expected to enter human Phase 1 trials in June under the NIH-NINDS Blueprint Development Program. Diabetic neuropathic pain is our principle clinical target, but EC5026 also shows promise as a non-addictive opioid replacement in many pain indications.

Movement to the clinic of soluble epoxide hydrolase inhibitor EC5026 as an analgesic for neuropathic pain and for use as an non-addictive opioid alternative

2019 Fall National Meeting

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