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 15 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 15 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 15 specifically targeted the
gut and showed efficacy in an IBD model, comparable to MCC950. These
findings highlight compound 15 as a promising lead for
novel oral NLRP3 inflammasome inhibitors.