Newly Designed and Improved Human Soluble Epoxide Hydrolase Inhibitors for Neuropathic pain

Abstract

Soluble epoxide hydrolase (sEH, EC 3.3.2.10) is responsible for metabolism of endogeneously derived fatty acid oxiranes, epoxyeicosatrienoic acids (EETs) to the corresponding diols, dihydroxyepoxyeicosatrienoic acids (DHETs). EETs are the products of arachidonic acid by cytochromes P450 epoxygenases and are key modulators involved in inflammation, pain and blood pressure. Inhibition of sEH that results in an increase in endogenous EETs, which have a significant effect on resolving inflammation and high blood pressure in rodent models. Therefore, the sEH has emerged as a pharmaceutical target for hypertension, inflammation and organ‐protection. Recently, we have demonstrated that elevation of epoxy‐fatty acid through sEH inhibition is able to resolve diabetic neuropathic pain in rodent.Over last decade, a series of N,N′‐disubstituted ureas has been developed to study the physiological effects of sEH inhibition in various murine and rodent models and their beneficial effects in several animals disease models has been demonstrated. To better study the effect of epoxy‐fatty acids on health, a set of new compounds with dramatically potency, a better solubility and an improved pharmacokinetic profiles has been synthesized, their PK‐ADME and efficacy on diabetic neuropathic pain will be determined and the results will be presented and discussed here.