New Highly Potent NLRP3 Inhibitors: Furanochalcone Velutone F Analogues.

The NLRP3 inflammasome has now emerged as one of the most appealing drug targets for many inflammation-related diseases. Velutone F, a natural NLPR3 inhibitor, identified in our previous study has been limited in application by its low in planta abundance, weak activity, and complicated synthetic routes. To address these needs, structural optimization of velutone F led to a series of novel NLRP3 inhibitors. Among them, compound exerted remarkable inhibitory activity with an IC value in the nanomolar range (251.1 nM) and was approximately 5-fold more potent than velutone F. Moreover, the synthesis method of was simple, easy to handle, and scalable. Compound could suppress NLRP3 inflammasome activation by attenuating ASC speck formation. Most importantly, compound reduced peritoneal neutrophil influx in mice and IL-1β in the spleen in the MSU-induced peritonitis in LPS-primed mouse model. Taken together, compound is a prospective lead compound in the discovery of NLRP3 inflammasome inhibitors.