soluble epoxide hydrolase (sEH, EC 3.3.2.10) is a major enzyme that metabolizes endogenously derived fatty acid epoxides, epoxyeicosatrienoic acids (EETs) to the corresponding 1,2-diols, dihydroxyepoxyeicosatrienoic acids (DHETs). EETs, the products of arachidonic acid from cytochromes P450 pathway, are key modulators involved in inflammation, pain and blood pressure. Inhibition of sEH resulted in an increase in in vivo level of EETs, have significant beneficial effects in several animal disease models. Therefore, the sEH has emerged as a pharmaceutical target. Recently, we demonstrated that elevation of epoxy-polyunsaturated fatty acids through sEH inhibition is able to resolve diabetic neuropathic pain in rodent. Over last decade, a series of N,N’-disubstituted ureas was developed as sEH inhibitors in order to study the physiological role of sEH and EET in various murine and rodent models. However, the use of inhibitors have been limited by poor drug-like properties from the central pharmacophore, N,N’-disubstituted ureas. Recently, it was reported that drugs with long residence time on target enzyme have better in vivo efficacy. Therefore, we developed a new assay to measure the residence time of the sEH inhibitor. With the new assay, we found that the new series of sEH inhibitors redesigned based on the recent crystal structure, have long residence time with much better drug-like properties and PK-ADME profile. Here, we will report and discuss the comparison of the in vivo efficacy and binding of sEH inhibitors with different residence time using diabetic neuropathic pain model. The results showed that there is a correlation betwee the residence time of sEH inhibitors and in vivo efficacy and binding.

Redesigned inhibitors of soluble epoxide hydrolase with improved drug-like properties and better target occupancy for the treatment of diabetic neuropathic pain

251st National Meeting (2016)

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