Design, Synthesis, and Pharmacological Characterization of a Potent Soluble Epoxide Hydrolase Inhibitor for the Treatment of Acute Pancreatitis

摘要

Acute pancreatitis(AP) is a potentially life-threateningillnesscharacterized by an exacerbated inflammatory response with limitedoptions for pharmacological treatment. Here, we describe the rationaldevelopment of a library of soluble epoxide hydrolase (sEH) inhibitorsfor the treatment of AP. Synthesized compounds were screened in vitro for their sEH inhibitory potency and selectivity,and the results were rationalized by means of molecular modeling studies.The most potent compounds were studied in vitro fortheir pharmacokinetic profile, where compound 28 emergedas a promising lead. In fact, compound 28 demonstrateda remarkable in vivo efficacy in reducing the inflammatorydamage in cerulein-induced AP in mice. Targeted metabololipidomicanalysis further substantiated sEH inhibition as a molecular mechanismof the compound underlying anti-AP activity in vivo. Finally, pharmacokinetic assessment demonstrated a suitable profileof 28 in vivo. Collectively, compound 28 displays strong effectiveness as sEH inhibitor with potentialfor pharmacological AP treatment.