Identification of a New, Potent, and Stable Tetrahydroquinoline-Based 5-LOX/sEH Dual Inhibitor with Polymodal Anti-Inflammatory Activity in Acute Pancreatitis.

Acute pancreatitis (AP) is a common, serious, pancreatic inflammation representing an unmet therapeutical need. Here, we report the design and synthesis of a series of compounds as dual 5-lipoxygenase (LOX)/soluble epoxide hydrolase (sEH) inhibitors aimed at favorably modulating inflammatory lipid mediator pathways. The tetrahydroquinoline-based compound 11 emerged as the most promising candidate, showing potent in vitro inhibition of both enzymes and satisfactory metabolic stability. Compound 11 was evaluated in a cerulein-induced murine model of AP, where it significantly reduced pancreatic damage, cellular infiltration, and edema formation. These effects led to beneficial modulation of LMs and attenuation of ferroptosis, concomitant with activation of the Nrf2 antioxidant pathway and upregulation of cytoprotective markers. Compound 11 ameliorated lung, liver, and kidney secondary damage, displaying an improved in vivo pharmacokinetic profile. Overall, these findings reveal compound 11 as a promising anti-inflammatory agent supporting dual 5-LOX/sEH inhibition, coupled with Nrf2 activation, as a viable strategy for AP.