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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Development of Dual Inhibitors of Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase with Tetrazole Core

Author(s): Sara Mehrandish, Elham Rezaee*, Anna Sedaghat, Elmira Heidarli, Nima Naderi and Sayyed Abbas Tabatabai*

Volume 19, Issue 10, 2023

Published on: 25 July, 2023

Page: [1037 - 1048] Pages: 12

DOI: 10.2174/1573406419666230718152453

Price: $65

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.

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Graphical Abstract

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