Design and Synthesis of sEH/HDAC6 Dual-Targeting Inhibitors for the Treatment of Inflammatory Pain

Soluble epoxide hydrolase (sEH) and HDAC6 mediate the
NF-κB
pathway in inflammatory responses, and their inhibitors exhibit powerful
anti-inflammatory and analgesic activities in treating both inflammation
and pain. Therefore, a series of dual-targeting inhibitors containing
urea or squaramide and hydroxamic acid moieties were designed and
synthesized, and their role as a new sEH/HDAC6 dual-targeting inhibitor
in inflammatory pain was evaluated in a formalin-induced mice model
and a xylene-induced mouse ear swelling model. Among them, compounds 28g and 28j showed the best inhibitory and selectivity
of sEH and HDAC6. Compound 28g had satisfactory pharmacokinetic
characteristics in rats. Following administration at 30 mg/kg, compound 28g exhibited more effective analgesic activity than either
an sEH inhibitor (GL-B437) or an HDAC6 inhibitor (Rocilinostat) alone and coadministration of both inhibitors.
Thus, these novel sEH/HDAC6 dual-targeting inhibitors exhibited powerful
analgesic activity in nociceptive behavior and are worthy of further
development.