Evaluation of the Therapeutic Potential of Sulfonyl Urea Derivatives as Soluble Epoxide Hydrolase (sEH) Inhibitors

Author:

Kundu, Biswajit

Dvorácskó, Szabolcs

Basu, Abhishek [ORCID]

Pommerolle, Lenny [ORCID]

Kim, Kyu Ah [ORCID]

Wood, Casey M

Gibbs, Eve

Behee, Madeline

Tarasova,Nadya

Cinar, Resat [ORCID]

Iyer, Malliga R [ORCID]
Author Address

Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), 5625 Fishers Lane, Rockville, MD 20852, USA., Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), 5625 Fishers Lane, Rockville, MD 20852, USA., Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), P.O. Box B, Frederick, MD 21702, USA.,

Abstract:

The inhibition of soluble epoxide hydrolase (sEH) can reduce the level of dihydroxyeicosatrienoic acids (DHETs) effectively maintaining endogenous epoxyeicosatrienoic acids (EETs) levels, resulting in the amelioration of inflammation and pain. Consequently, the development of sEH inhibitors has been a prominent research area for over two decades. In the present study, we synthesized and evaluated sulfonyl urea derivatives for their potential to inhibit sEH. These compounds underwent extensive in vitro investigation, revealing their potency against human and mouse sEH, with 4f showing the most promising sEH inhibitory potential. When subjected to lipopolysaccharide (LPS)-induced acute lung injury (ALI) in studies in mice, compound 4f manifested promising anti-inflammatory efficacy. We investigated the analgesic efficacy of sEH inhibitor 4f in a murine pain model of tail-flick reflex. These results validate the role of sEH inhibition in inflammatory diseases and pave the way for the rational design and optimization of sEH inhibitors based on a sulfonyl urea template.

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