Abstract
The NLRP3 inflammasome has been extensively studied in recent years and its aberrant activation can exacerbate inflammatory responses, contributing to various diseases. MCC950, a sulfonylurea drug, is a potent selective inhibitor of the NLRP3 inflammasome. However, its clinical development was halted due to hepatotoxicity, and studies have indicated significant reduction in activity among its metabolites. Building upon MCC950, we referenced substitution sites of NP3-146 for structural modifications aimed at addressing potential metabolism-related issues. Consequently, we synthesized a series of sulfonylurea derivatives. Ultimately, the optimized compound C4 exhibited a remarkable 80.39 % inhibition of IL-1β at 2 μM, with an IC50 value of 0.805 μM. In conclusion, compound C4 shows potential as a lead compound and warrants further development as an anti-inflammatory NLRP3 inhibitor.
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