Design, synthesis and biological evaluation of phenyl vinyl sulfone based NLRP3 inflammasome inhibitors

Abstract

As the vital component of innate immune system, the NLRP3 inflammasome is implicated in the onset and progression of a variety of inflammatory diseases and has emerged as an attractive drug target. Herein a series of novel phenyl vinyl sulfone based NLRP3 inflammasome inhibitors were designed, synthesized and biologically characterized. The most potent two hits 7a and 5b showed inhibition on the NLRP3 inflammasome with the IC₅₀ of 1.83 ± 0.28 µM and 0.91 ± 0.06 µM, respectively. Further characterization confirmed their inhibition of NLRP3-mediated IL-1β release in vivo. Collectively, our findings encourage further research of more potent inhibitors based on this chemical scaffold.

Keywords: IL-1β; NLRP3 inflammasome inhibitor; Phenylvinyl sulfone; activity evaluation.