Discovery of dronedarone and its analogues as NLRP3 inflammasome inhibitors with potent anti-inflammation activity. (15th August 2021)

• Record Type: Journal Article
• Authors: Chen, Hao; Chen, Xiuhui; Sun, Ping; Wu, Dan; Yue, Hu; Pan, Jintao; Li, Xinxuan; Zhang, Cheng; Wu, Xinyi; Hua, Lei; Hu, Wenhui; Yang, Zhongjin
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 46(2021)
• Publication Date: 2021-08-15
• Subjects: NLRP3 inflammasome -- Inhibitor -- IL-1β -- Dronedarone; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128160
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 μM against IL-1 β 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 μM) against IL-1 β release. Notably, treatment with 8c could significantly inhibit NLRP3-mediated IL-1 β 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.