Soluble epoxide hydrolase inhibitors: an overview and patent review from the last decade

ABSTRACT

Introduction

Biological effects mediated by the CYP450 arm of arachidonate cascade implicate the enzyme-soluble epoxide hydrolase (sEH) in hydrolyzing anti-inflammatory epoxy fatty acids to pro-inflammatory diols. Hence, inhibiting the sEH offers a therapeutic approach to treating inflammatory diseases. Over three decades of work has shown the role of sEH inhibitors (sEHis) in treating various disorders in rodents and larger veterinary subjects. Novel chemical strategies to enhance the efficacy of sEHi have now appeared.

Areas covered

A comprehensive review of patent literature related to soluble epoxide hydrolase inhibitors in the last decade (2010–2021) is provided.

Expert opinion

Soluble epoxide hydrolase (sEH) is an important enzyme that metabolizes the bioactive epoxy fatty acids (EFAs) in the arachidonic acid signaling pathway and converts them to vicinal diols, which appear to be pro-inflammatory. Inhibition of sEH hence offers a mechanism to increase in vivo epoxyeicosanoid levels and resolve pro-inflammatory pathways in disease states. Significant efforts in the field have led to potent single target as well as multi-target inhibitors with promising in vitro and widely encompassing in vivo activities. Successful clinical translation of compounds targeting sEH inhibition will further validate the promised therapeutic potential of this pathway in treating human diseases.

KEYWORDS:

• EETs
• enzymatic activity
• hypertension
• inflammatory diseases
• sEH inhibitor
• soluble epoxide hydrolase
• sEH-P

Article highlights

• Since the discovery and elucidation of the role of soluble epoxide hydrolase enzyme (sEH), C-terminal domain in the arachidonic acid metabolism cascade, extensive strategies have appeared to target this pathway by inhibiting sEH (sEHi) for therapeutic gain

• While initial research was focused on substituted urea-based analogues as, the last decade has witnessed several drug-discovery campaigns involving non-urea scaffolds as sEHi

• Dual-target synergism with sEHi has led to potent compounds with promising translational potential

• The field is still evolving with increasing number of approaches appearing to target the N-terminal phosphatase domain of the bifunctional sEH enzyme

• Agents based on the soluble epoxide hydrolase inhibition are in clinical trials although no clinical use of these has yet been approved.

Declaration of interests

MR Iyer and B Kundu are co-inventors on a pending patent application related to compounds targeting soluble epoxide hydrolase inhibitors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A peer reviewer of this manuscript has worked with EicOsis on the development of epoxide hydrolase inhibitors for clinical use. All other peer reviewers of this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the Intramural Program/Division of Intramural Clinical and Biological Research (DICBR), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health.