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<p>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 <b>7f</b> was a more effective inhibitor with IC<sub>50</sub> values of 1.2&#xa0;nM and 18&#xa0;nM on FAAH and sEH enzymes, respectively. The results of the <i>in-vitro</i> evaluation were significantly consistent with the docking results.</p>

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

  • 期刊论文

  • 发表日期：

    2025年7月7日

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  • Maryam Salehi,
  • Anna Sedaghat,
  • Maryam Bayanati,
  • Mohammad Ismail Mahboubi Rabbani,
  • Elham Rezaee,
  • Sayyed Abbas Tabatabai

摘要

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.