4.5 Article

Discovery of dronedarone and its analogues as NLRP3 inflammasome inhibitors with potent anti-inflammation activity

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出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2021.128160

关键词

NLRP3 inflammasome; Inhibitor; IL-1 beta; Dronedarone

资金

  1. National Natural Science Foundation of China (NSFC) [81803364, 81872743]

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Compound 8c was found to significantly inhibit NLRP3-mediated IL-1 beta release and alleviate peritoneal inflammation in a mouse model. It is a promising lead compound for further chemical development as a NLRP3 inhibitor with anti-inflammation effects.
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.

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