Discovery Of Dronedarone And Its Analogues As Nlrp3 Inflammasome Inhibitors With Potent Anti-Inflammation Activity

Inhibiting NLRP3 inflammasome activation is a prospective therapeutic strategy for uncontrolled inflammatory diseases. It is the first time that dronedarone, a multiply ion channel blocker, was identified as a NLRP3-inflammasome inhibitor with an IC50 value of 6.84 mu M against IL-1 beta release. A series of novel 5-amide benzofuran derivatives were designed and synthesized as NLRP3-inflammasome inhibitors. Compound 8c showed slightly increased activity (IC50 = 3.85 mu M) against IL-1 beta release. Notably, treatment with 8c could significantly inhibit NLRP3-mediated IL-1 beta release and ameliorate peritoneal inflammation in a mouse model of sepsis. Collectively, 8c is a promising lead compound for further chemical development as a NLRP3 inhibitor with anti-inflammation effects.