Structure–Stability Relationship of NLRP3 Inflammasome-Inhibiting Sulfonylureas

In recent drug development efforts, particular emphasis has been devoted to the chemical interference with the NLRP3 inflammasome. A series of 12 tailored sulfonylureas was designed, prepared through convergent syntheses with a final sodium hydride-promoted reaction of isocyanates and sulfonamides, and subjected to a systematic, high-performance liquid chromatography-based survey of the chemical stability, a critical issue of sulfonylureas in terms of preparation, storage, and application. NLRP3 binding was determined by surface plasmon resonance spectroscopy. Sulfonylurea 2 was identified to be equipotent and similarly stable compared to the prototypical NLRP3 inhibitor MCC950.