Polynitrogen-containing compounds as multi-target sEH/FAAH inhibitors: Structure-activity relationship and pharmacological studies

作者：Amanda Tsang, Cassandra Yuan, Manuel Berumen, Leah Duong, Karen Rocío Plata-Gómez, Shelby Seely, Alex Salgado, Adim Rai, Jo Vistosa, Edith Morales Munoz, Marcos Ortega, Christophe H.P. Morisseau, Bruce D. Hammock, Jake E. Zuckerman, Joseph Yount, Davin G. Piercey, Ram Kandasamy, Stevan Pecic · 发表于：Bioorganic & Medicinal Chemistry · 年份：2025 · DOI：10.1016/j.bmc.2025.118495 · 被引用次数：3 · 研究领域：Eicosanoids and Hypertension Pharmacology、Fatty Acid Research and Health、Antiplatelet Therapy and Cardiovascular Diseases

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 exhibit...