Discovery of Triazinone Derivatives as Novel, Specific, and Direct NLRP3 Inflammasome Inhibitors for the Treatment of DSS-Induced Ulcerative Colitis

NLRP3 is an intracellular sensor protein that causes
inflammasome
formation and pyroptosis in response to a wide range of stimuli. Aberrant
activation of NLRP3 inflammasome has been implicated in various chronic
inflammatory diseases, making it a promising target for therapeutic
intervention. In this work, a series of novel triazinone inhibitors
of NLRP3 inflammasome were designed and synthesized. Compound L38 was identified for its excellent activity and acceptable
metabolic stability among 41 compounds. Additionally, mechanism studies
indicated that L38 inhibited NLRP3 inflammasome activation
and pyroptosis by suppressing gasdermin D cleavage, ASC oligomerization,
and NLRP3 inflammasome assembly while leaving mitochondrial ROS production,
lysosome damage, and chloride/potassium efflux unaffected. Further
investigation revealed that L38 could bind to the NACHT
domain to exert inflammatory properties. Importantly, L38 exhibited positive therapeutic effects in DSS-induced ulcerative
colitis mouse model. Taken together, this study presents a promising
inhibitor of NLRP3 inflammasome deserving further investigation.