Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative

This
report describes the development of an orally active analgesic
that resolves inflammation and neuropathic pain without the addictive
potential of opioids. EC5026 acts on the cytochrome P450 branch of
the arachidonate cascade to stabilize epoxides of polyunsaturated
fatty acids (EpFA), which are natural mediators that reduce pain,
resolve inflammation, and maintain normal blood pressure. EC5026 is
a slow-tight binding transition-state mimic that inhibits the soluble
epoxide hydrolase (sEH) at picomolar concentrations. The sEH rapidly
degrades EpFA; thus, inhibiting sEH increases EpFA in vivo and confers beneficial effects. This mechanism addresses disease
states by shifting endoplasmic reticulum stress from promoting cellular
senescence and inflammation toward cell survival and homeostasis.
We describe the synthesis and optimization of EC5026 and its development
through human Phase 1a trials with no drug-related adverse events.
Additionally, we outline fundamental work leading to discovery of
the analgesic and inflammation-resolving CYP450 branch of the arachidonate
cascade.