Novel Soluble Epoxide Hydrolase Inhibitors Featuring a 2‐Oxaadamantane Moiety: Synthesis, <i>in vitro</i> Profiling and <i>in vivo</i> Evaluation in Murine Models of Acute Pancreatitis (2018)

Epoxyeicosatrienoic acids (EETs) are endogenous chemical mediators derived from arachidonic acid. These EETs show anti‐inflammatory, antihypertensive, analgesic, angiogenic, and antiatherosclerotic effects.1 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. Potent, orally bioavailable sEH inhibitors (sEHI) have been developed, several of them featuring an adamantane scaffold, including AR9281 that proved to be safe in human clinical trials.2 Our research group is working in novel sEHI bearing adamantane‐like scaffolds. 2‐oxaadamantane arose as a suitable replacement moiety since the derivatives bearing it maintained the inhibitory activity on the target and increased solubility.3 Herein we report the synthesis and structure‐activity relationships of a series of novel 2‐oxaadamantane‐based ureas with improved drug‐like properties. Several of them reduced the levels of endoplasmic reticulum (ER) stress and inflammatory markers in an in vitro model of cerulein‐induced acute pancreatitis (AP) in the rat pancreatic acinar cell line AR42J. Further in vitro profiling (human and mice microsomal stability, solubility, cytotoxicity, cytochromes inhibition, Caco‐2 permeability, selectivity, hERG inhibition) and pharmacokinetics (PK) and maximum tolerated dose (MTD) studies allowed us to select a candidate for in vivo studies in two mice models of cerulein‐induced AP.4 We found that cerulein‐induced AP significantly increased sEH activity,5 and we noted that intraperitoneal administration of our inhibitor restored sEH activity to normality. We found that the sEHI, administered before or after induction of AP, significantly reduced, in a dose‐dependent manner, pancreatic mRNA abundance of the inflammatory cytokines tumor necrosis factor‐α, interleukin Il‐1β and Il‐6, and the chemokine MCP‐1. Additionally, the levels of the ATF‐3 ER stress marker were also reduced in the sEHI‐treated mice. In summary, these results suggest that 2‐oxaadamantane‐based sEHI may be of clinical interest for preventing and treating acute pancreatitis. Support or Funding Information Financial support from Ministerio de Economía y Competitividad (Projects SAF2014‐57094‐R and SAF2015‐64146‐R), CaixaImpulse 2015 Programme and Spain EIT Health proof of concept 2016 are acknowledged. R. L. and E. V. thank the Ministerio de Educación, Cultura y Deporte (FPU program), and the IBUB, respectively, for PhD Grants. S.C. and E. P. thank the Universitat de Barcelona for PhD Grants. The authors thank Bruce D. Hammock and Christophe Morisseau (UCD) for advice when we started running up the sEHI assay kit and for stimulating discussions. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .