Design and Synthesis of Novel sEH Inhibitors for the Treatment of Inflammatory Bowel Disease

The treatment of inflammatory bowel disease (IBD) may rely on the comprehensive regulation of immune inflammatory factors to reach a favorable therapeutic effect. In the current study, we discovered a series of sEH inhibitors containing a squaryl sulfonamide scaffold that potently inhibited the primary proinflammatory signaling pathways of NF-κB. Especially, lead compounds <b>A1</b> and <b>A9</b> showed potent inhibitory activities against sEH (<b>A1</b> and <b>A9</b>; hsEH IC₅₀ = 0.1 nM, msEH IC₅₀ = 0.1 nM). The compound <b>A1</b> had medium pharmacokinetic characteristics in rats. <i>In vivo</i>, <b>A1</b> showed a strong anti-inflammatory activity in acute enteritis models and decreased the release of various proinflammatory factors, including IL-6 and TNF-α. More importantly, <b>A1</b> maintained the integrity of the intestinal barrier. Besides, <b>A1</b> possessed good <i>in vivo</i> tolerability in subacute safety evaluation. Collectively, this study provided valuable lead compounds for the treatment of IBD that were worthy of further development.