Discovery of Novel Sulfonylurea NLRP3 Inflammasome Inhibitor for the Treatment of Multiple Inflammatory Diseases

NLRP3 inflammasome is critical in innate immunity and inflammatory responses. A series of novel sulfonylurea-based NLRP3 inflammasome inhibitors was designed and synthesized. Notably, compound <b>15</b> exhibited the potent NLRP3 inhibitory activity, effectively suppressing IL-1β secretion in THP-1 (IC₅₀ = 23 nM), demonstrating better efficacy compared to MCC950. It selectively inhibits NLRP3 activation by disrupting inflammasome assembly, with no effect on NLRC4 or AIM2 inflammasomes. Molecular docking showed that the 1-methyl-4-(methylamino)piperidine moiety forms a novel hydrogen bond with Asp662 in the hydrophilic region of NLRP3. Additionally, compound <b>15</b> displayed excellent pharmacokinetic properties with 99.6% oral bioavailability in mice. It exhibited superior efficacy in acute peritonitis and diabetic kidney disease models, surpassing MCC950. Tissue distribution studies confirmed that compound <b>15</b> specifically targeted the gut and showed efficacy in an IBD model, comparable to MCC950. These findings highlight compound <b>15</b> as a promising lead for novel oral NLRP3 inflammasome inhibitors.