Selection of Potent Inhibitors of Soluble Epoxide Hydrolase for Usage in Veterinary Medicine.

Diyala S Shihadih,Sean D Kodani,Kin Sing Stephen Lee,Sung-Hee Hwang,Bruce D Hammock,Briana Hamamoto,Vengai Mavangira,Christophe Morisseau,Alonso Guedes,Todd R Harris

doi:10.3389/fvets.2020.00580

Abstract

The veterinary pharmacopeia available to treat pain and inflammation is limited in number, target of action and efficacy. Inhibitors of soluble epoxide hydrolase (sEH) are a new class of anti-inflammatory, pro-resolving and analgesic drugs being tested in humans that have demonstrated efficacy in laboratory animals. They block the hydrolysis, and thus, increase endogenous concentrations of analgesic and anti-inflammatory signaling molecules called epoxy-fatty acids. Here, we screened a library of 2,300 inhibitors of the sEH human against partially purified feline, canine and equine hepatic sEH to identify inhibitors that are broadly potent among species. Six very potent sEH inhibitors (IC50 < 1 nM for each enzyme tested) were identified. Their microsomal stability was then measured in hepatic extracts from cat, dog and horse, as well as their solubility in solvents suitable for the formulation of drugs. The trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB, 1,728) appears to be the best compromise between stability and potency across species. Thus, it was selected for further testing in veterinary clinical trials of pain and inflammation in animals.

Highlights

Pain management is central to the effective treatment of both human and veterinary patients
Chronic laminitis in horses is an extremely painful condition that too often leads to euthanasia due to the inability of currently available analgesics to adequately control pain [3]. Osteoarthritis is another chronic painful condition, especially in elderly cats and dogs, that can be difficult to Veterinary Soluble Epoxide Hydrolase Inhibitor manage with currently available analgesics
The endogenous hydrolysis of the epoxy-eicosatrienoic acids (EETs) to their corresponding diols by soluble epoxide hydrolase reduces their biological activity [8]. Both in vitro and in vivo studies have demonstrated that the modulation of chronic inflammation and neuronal pain by EETs is inversely dependent on the extent of their hydrolysis by sEH [7,8,9]

Summary

INTRODUCTION

Pain management is central to the effective treatment of both human and veterinary patients. The main class of veterinary drugs used to reduce pain and inflammation in animals, including horses, cats, and dogs, are non-steroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase inhibitors (COXIBs) and corticosteroids. Veterinary Soluble Epoxide Hydrolase Inhibitor manage with currently available analgesics. It cannot be treated with NSAIDs or COXIBs chronically because of adverse side effects, such as liver toxicity and gastric ulceration [4, 5]. The endogenous hydrolysis of the EETs to their corresponding diols by soluble epoxide hydrolase (sEH) reduces their biological activity [8] Both in vitro and in vivo studies have demonstrated that the modulation of chronic inflammation and neuronal pain by EETs is inversely dependent on the extent of their hydrolysis by sEH [7,8,9]. Microsomal stability of potent compounds was tested, as well as the solubility of the selected inhibitor in solvents typically used in the formulation of drugs

MATERIALS AND METHODS

RESULTS

DISCUSSION

DATA AVAILABILITY STATEMENT