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