Synthesis of a New Family of Soluble Epoxide Hydrolase Inhibitors, in vitro Profiling and in vivo Evaluation in a Murine Model of Acute Pancreatitis

Abstract

Acute pancreatitis (AP) is a serious and life‐threatening inflammatory disease and arises as one of the most common gastrointestinal disorders worldwide. Aside from palliative treatments (analgesics, hydration, antibiotics), there is no standard therapeutic strategy for reducing inflammation in AP.Epoxyeicosatrienoic acids (EETs) are endogenous chemical mediators derived from arachidonic acid that show anti‐inflammatory, antihypertensive, analgesic, angiogenic, and anti‐atherosclerotic effects. Soluble epoxide hydrolase (sEH) converts EETs to their corresponding dihydroxyeicosatrienoic acids, whereby the biological effects of EETs are diminished, eliminated, or altered. It has been proposed that inhibition of sEH may have therapeutic effects in various inflammatory diseases.Recently, it has been studied the effects of pharmacological inhibition of sEH using TPPU, a potent sEH inhibitor (sEHI), on cerulein‐ and arginine‐induced AP murine models. The results showed a reduction of circulating and pancreatic levels of mRNA of different inflammatory cytokines and diminution of the endoplasmic reticulum stress and cell death.Herein we report the synthesis and structure‐activity relationships of a series of novel sEHI with excellent drug‐like properties. Most of them were endowed with low nanomolar or even subnanomolar IC50 values against the human and murine sEH enzyme. They also inhibited the sEH in the rat pancreatic acinar cell line AR42J. Further in vitro profiling (human and mice microsomal stability, solubility, CYP inhibition, selectivity) and pharmacokinetic studies allowed us to select a candidate for an in vivo efficacy study in a mice model of cerulein‐induced AP.We found that our candidate, administered intraperitoneally (3 mg/Kg) after the induction of AP, significantly reduced pancreatic mRNA abundance of the inflammatory cytokines tumor necrosis factor‐α, interleukins Il‐1β, Il‐6 and Il‐10; the enzymes myeloperoxidase, pancreatic amylase and pancreatic trypsin, and the chemokines MCP‐1 and CXC1.In summary, these novel results and the previously reported studies using other sEHI, strongly suggest that sEH may be a target of interest for treating AP.Support or Funding InformationWe thank Ministerio de Economía y Competitividad (Agencia Estatal de Investigación) and Fondo Europeo de Desarrollo Regional (MINECO‐FEDER) (SAF2017‐82771 and SAF2015‐64146‐R7), Generalitat de Catalunya (2017SGR106), Spain EIT Health (Proof of concept 2016) and Fundació Bosch i Gimpera, Universitat de Barcelona (F2I grant) for funding. S.C. thanks the Universitat de Barcelona for a PhD Grant (APIF program). This work was supported in part by the National Institute of Environmental Health Sciences grant R01‐ES002710, and Superfund Research Program P42 ES04699.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.