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

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 M9. M9 exhibits selective inhibition of HDAC6
over class I HDACs in cells. M9 shows good microsomal
stability, moderate plasma protein binding rate, and oral bioavailability. M9 exhibited a strong analgesic effect in vivo, and its analgesic
tolerance was better than gabapentin. M9 improved the survival time of mice treated with lipopolysaccharide
(LPS) and reversed the levels of inflammatory factors induced by LPS
in mouse plasma. M9 represents the first sEH/HDAC6 dual
inhibitors with in vivo antineuropathic pain and anti-inflammation.