发现具有强效抗炎活性的 NLRP3 炎性体抑制剂决奈达隆及其类似物。
Discovery of dronedarone and its analogues as NLRP3 inflammasome inhibitors with potent anti-inflammation activity.
机构信息
Key Laboratory of Molecular Target & Clinical Pharmacology and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.
Key Laboratory of Molecular Target & Clinical Pharmacology and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.
出版信息
Bioorg Med Chem Lett. 2021 Aug 15;46:128160. doi: 10.1016/j.bmcl.2021.128160. Epub 2021 May 29.
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 IC value of 6.84 μM against IL-1β release. A series of novel 5-amide benzofuran derivatives were designed and synthesized as NLRP3-inflammasome inhibitors. Compound 8c showed slightly increased activity (IC = 3.85 μM) against IL-1β release. Notably, treatment with 8c could significantly inhibit NLRP3-mediated IL-1β 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.
抑制 NLRP3 炎性小体的激活是治疗失控性炎症性疾病的一种有前景的治疗策略。多离子通道阻滞剂决奈达隆首次被鉴定为 NLRP3 炎性小体抑制剂，其对白细胞介素-1β（IL-1β）释放的 IC 值为 6.84μM。设计并合成了一系列新型 5-酰胺苯并呋喃衍生物作为 NLRP3 炎性小体抑制剂。化合物 8c 对白细胞介素-1β（IL-1β）释放的活性略有增加（IC = 3.85μM）。值得注意的是，8c 的治疗可显著抑制 NLRP3 介导的白细胞介素-1β（IL-1β）释放，并改善脓毒症小鼠模型中的腹膜炎症。总之，8c 是一种有前途的先导化合物，可作为一种具有抗炎作用的 NLRP3 抑制剂进一步进行化学开发。
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