Novel dual inhibitor targeting FAAH and sEH: Design, synthesis, and in-vitro evaluation of oxadiazole analogues

Fatty acid amide hydrolase (FAAH) enzyme, as a potential therapeutic target for the treatment of pain and inflammation, is responsible for decomposing fatty acid amides like endocannabinoids. One attractive technique for increasing the efficacy of FAAH inhibitors is to generate antinociception and anti-inflammatory effects via another route, such as soluble epoxide hydrolase (sEH) inhibition, at the same time. In this study, two series of structures bearing oxadiazole rings as dual inhibitors of FAAH/sEH were designed, synthesized, and biologically evaluated. Most compounds showed an excellent affinity towards the active sites of both enzymes compared to the standard ligands of JZL-195 and AUDA. Among all the synthesized compounds, compound 7f was a more effective inhibitor with IC₅₀ values of 1.2 nM and 18 nM on FAAH and sEH enzymes, respectively. The results of the in-vitro evaluation were significantly consistent with the docking results.