Key result
Dual FAAH/sEH inhibitor 4m potently inhibits both targets but significantly depresses voluntary running in rats.
Why the study?
Inhibition of sEH and FAAH pathways represents a novel non-opioid strategy for inflammatory pain, motivating exploration of heterocyclic moieties to maintain inhibition potency while increasing metabolic stability and solubility.
p-value: p=0.03
Although analog 4m is an extremely potent dual inhibitor of sEH and FAAH in vitro, it produces unexpected and undesirable depressions in voluntary locomotor behavior in vivo, emphasizing the importance of early behavioral screening in non-opioid pain drug discovery.
May signal locomotor liabilities for dual FAAH/sEH inhibitors; leaves open whether analogs can retain potency without behavioral effects.
Both soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) are involved in degradation of anti-inflammatory and antinociceptive lipids, thus inhibition of these enzymatic pathways represents a novel strategy in the discovery of non-opioid drugs for treating inflammatory pain. We previously discovered several multi-targeted designed ligands and described a pharmacophore necessary for inhibition of both sEH and FAAH. The potential for optimization on the left side of the pharmacophore led us to exploration of different heterocyclic moieties with the hope to keep strong inhibition potencies, but to increase the metabolic stability and solubility of new analogs. Eighteen analogs containing various substituted and unsubstituted pyrimidinyl-, quinoxalinyl- and tetrazolyl- rings are synthesized and tested for inhibition potency in human FAAH, and human, rat and mouse sEH. The structure-activity relationship study revealed quinoxalinyl- analog 4 m , the most potent dual inhibitor reported to date, with IC 50 values of 2.9 nM in human FAAH and 0.7 nM, 39.1 nM and 0.3 nM in human, mouse and rat sEH, respectively. 4 m showed no binding to opioid and most serotonin receptors and was tested in the human, mouse and rat liver microsomes stability assays where it exhibited good and/or moderate clearance rates. Lastly, we evaluated 4 m in vivo in a wheel running assay to determine its effects on voluntary locomotor behavior. Both 4 m and the traditional opioid morphine exhibited significant depression of wheel running after intraperitoneal administration indicating that 4 m may produce undesirable behavioral effects, which will be the basis for future studies. • Eighteen compounds with heteroaromatic moieties were tested for dual sEH/FAAH inhibition. • Pyrimidine ring improved solubility but led to loss in the activity. • Introduction of tetrazolyl-moiety led to excellent potency in sEH, but no FAAH activity. • Quinoxaline ring resulted in enhanced inhibition potency without binding to opioid receptors. • The dual inhibitor 4 m decreased voluntary wheel running activity to a similar extent to morphine in rats.
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Yuan et al. (2025) studied Inflammation and Pain. Compound 4m (quinoxalinyl analog) vs. Vehicle and Morphine was evaluated on Enzymatic inhibition potency (IC50) and voluntary wheel running revolutions (p=0.03). The novel compound 4m exhibited potent dual inhibition of human FAAH (IC50 2.9 nM) and sEH (IC50 0.7 nM), but significantly depressed voluntary wheel running in rats compared to vehicle.
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