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

Bruce D Hammock, Cindy B. McReynolds, Karen Wagner, Alan Buckpitt, Irene Cortes-Puch, Glenn Croston, Kin Sing Stephen Lee, Jun Yang, William K. Schmidt, Sung Hee Hwang

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1856-1872
Number of pages17
JournalJournal of medicinal chemistry
Volume64
Issue number4
DOIs
StatePublished - Feb 25 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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