Title:Development of Dual Inhibitors of Soluble Epoxide Hydrolase/Fatty Acid
Amide Hydrolase with Tetrazole Core
Volume: 19
Issue: 10
Author(s): Sara Mehrandish, Elham Rezaee*, Anna Sedaghat, Elmira Heidarli, Nima Naderi and Sayyed Abbas Tabatabai*
Affiliation:
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences,
Tehran, Iran
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences,
Tehran, Iran
Keywords:
Synthesis, tetrazole, soluble epoxide hydrolase, fatty acid amide hydrolase, pain, inflammatory.
Abstract:
Introduction: The attractive biological actions of the eicosatrienoic acids (EETs) and
endocannabinoids (eCBs) are terminated by means of enzymatic hydrolysis via soluble epoxide hydrolase
(sEH) and fatty acid amide hydrolase (FAAH) enzymes. Simultaneous inhibition of both
enzymes is considered a novel approach in the treatment of inflammatory and neuropathic pain.
Methods: In this study, a novel series of tetrazole derivatives as dual sEH/FAAH inhibitors were
designed, synthesized, and biologically evaluated. Compounds 6c, 7d, and 8a, the most potent inhibitors
against FAAH and sEH enzymes with acceptable IC50 values, significantly decreased carrageenan-
induced paw edema 5h after carrageenan injection compared to the control group compound. In
addition, compound 7d exhibited a significant reduction in pain scores compared to the control
group.
Results: Docking studies showed that the presented dual inhibitors could bind to the essential residues
in the catalytic sites of both enzymes. In silico prediction of several pharmacokinetic properties
suggests that these dual inhibitors could potentially be orally active agents.
Conclusion: These structures will be a valuable scaffold to develop soluble epoxide hydrolase inhibitors
with dual potency towards fatty acid amide hydrolase.