Design and Synthesis of Dual-Targeting Inhibitors of sEH and HDAC6 for the Treatment of Neuropathic Pain and Lipopolysaccharide-Induced Mortality

Abstract

Epoxyeicosatrienoic acids with anti-inflammatory effects are inactivated by soluble epoxide hydrolase (sEH). Both sEH and histone deacetylase 6 (HDAC6) inhibitors are being developed as neuropathic pain relieving agents. Based on the structural similarity, we designed a new group of compounds with inhibition of both HDAC6 and sEH and obtained compound <b>M9</b>. <b>M9</b> exhibits selective inhibition of HDAC6 over class I HDACs in cells. <b>M9</b> shows good microsomal stability, moderate plasma protein binding rate, and oral bioavailability. <b>M9</b> exhibited a strong analgesic effect in vivo, and its analgesic tolerance was better than <b>gabapentin</b>. <b>M9</b> improved the survival time of mice treated with lipopolysaccharide (LPS) and reversed the levels of inflammatory factors induced by LPS in mouse plasma. <b>M9</b> represents the first sEH/HDAC6 dual inhibitors with in vivo antineuropathic pain and anti-inflammation.