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

Acute pancreatitis (AP) is a potentially life-threatening illness characterized by an exacerbated inflammatory response with limited options for pharmacological treatment. Here, we describe the rational development of a library of soluble epoxide hydrolase (sEH) inhibitors for 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 for their pharmacokinetic profile, where compound 28 emerged as a promising lead. In fact, compound 28 demonstrated a remarkable in vivo efficacy in reducing the inflammatory damage in cerulein-induced AP in mice. Targeted metabololipidomic analysis further substantiated sEH inhibition as a molecular mechanism of the compound underlying anti-AP activity in vivo. Finally, pharmacokinetic assessment demonstrated a suitable profile of 28 in vivo. Collectively, compound 28 displays strong effectiveness as sEH inhibitor with potential for pharmacological AP treatment.

Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization.

The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH). In silico analysis of an in-house library identified nine compounds as potential 5-LOX inhibitors. Enzymatic and cellular assays revealed the indoline derivative 43 as a notable 5-LOX inhibitor, guiding the design of new analogues. These compounds underwent extensive in vitro investigation revealing dual 5-LOX/sEH inhibitors, with 73 showing the most promising activity (IC50s of 0.41 ± 0.01 and 0.43 ± 0.10 µM for 5-LOX and sEH, respectively). When challenged in vivo in zymosan-induced peritonitis and experimental asthma in mice, compound 73 showed remarkable anti-inflammatory efficacy. These results pave the way for the rational design of 5-LOX/sEH dual inhibitors and for further investigation of their potential use as anti-inflammatory agents.