Structure-based design and synthesis of sulfonylureas as novel NLRP3 inhibitors for Alzheimer's disease

Alzheimer's disease (AD) remains an incurable neurodegenerative condition that poses a threat to humanity. Immune signaling in the brain, particularly the NLR family pyrin domain containing 3 (NLRP3), is currently targeted for AD treatment. Based on the crystal structure of the NACHT domain of NLRP3 and its renowned inhibitor MCC950, we designed and synthesized nineteen sulfonylurea compounds and evaluated their capacity to inhibit caspase-1 and interleukin-1 beta (IL-1 beta). Of these, nine were selected for measuring their IC50 for caspase-1 and cytotoxicity analysis. Finally, three compounds were chosen to assess their inhibitory effect on IL-1 beta in mice. The results showed that compound 5m had a superior ability to reduce IL-1 beta levels in the brain compared to MCC950 at a lower dosing concentration, indicating that 5m has the potential to penetrate the blood-brain barrier (BBB) and inhibit inflammation both in vitro and in vivo. Docking studies of compound 5m on NLRP3 revealed a binding mode similar to MCC950. These findings suggest that compound 5m holds promise as an NLRP3 inhibitor for AD treatment.