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Novel Sulfonylurea-Based NLRP3 Inflammasome Inhibitor for Efficient Treatment of Nonalcoholic Steatohepatitis, Endotoxic Shock, and Colitis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-09-11 , DOI: 10.1021/acs.jmedchem.3c00894
Zhuoyue Li 1, 2 , Yiming Chen 1 , Xiaolin Jiang 1, 3 , Penghui Lu 1 , Chengli Wang 2 , Zhimin Li 2 , Xinyue Yu 2 , Zixuan Yang 1 , Shumin Ma 1, 2 , Shanshan Du 3 , Zhengfu Tai 2 , Xiaoyang Li 1, 2 , Siqi Zhang 1, 2 , Yuqi Jiang 1, 2 , Chong Qin 1, 2, 4
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-09-11 , DOI: 10.1021/acs.jmedchem.3c00894
Zhuoyue Li 1, 2 , Yiming Chen 1 , Xiaolin Jiang 1, 3 , Penghui Lu 1 , Chengli Wang 2 , Zhimin Li 2 , Xinyue Yu 2 , Zixuan Yang 1 , Shumin Ma 1, 2 , Shanshan Du 3 , Zhengfu Tai 2 , Xiaoyang Li 1, 2 , Siqi Zhang 1, 2 , Yuqi Jiang 1, 2 , Chong Qin 1, 2, 4
Affiliation
The NLRP3 inflammasome is a critical component of innate immunity involved in the pathophysiology of various inflammatory diseases. In this study, we designed and synthesized a series of NLRP3 inflammasome inhibitors based on MCC950. Specifically, we optimized the furan moiety, which is considered to be potentially associated with drug-induced liver injury. The representative inhibitor N14, 4-(2-(dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonamide, not only maintains the NLRP3 inhibitory activity of MCC950 with IC50 of 25 nM but also demonstrates improved tolerability in human hepatic cells line and mouse primary hepatocytes. In addition, N14 exhibits superior pharmacokinetic properties, with an oral bioavailability of 85.2%. In vivo studies demonstrate that N14 is more effective than MCC950 in multiple NLRP3-related animal model diseases, including nonalcoholic steatohepatitis, lethal septic shock, and colitis. Our research has provided a lead compound that directly targets the NLRP3 inflammasome and can be developed as a novel therapeutic candidate for NLRP3-driven diseases.
中文翻译:
新型磺酰脲基 NLRP3 炎症小体抑制剂可有效治疗非酒精性脂肪性肝炎、内毒素性休克和结肠炎
NLRP3 炎症小体是先天免疫的重要组成部分,参与各种炎症性疾病的病理生理学。在本研究中,我们基于MCC950设计并合成了一系列NLRP3炎症小体抑制剂。具体来说,我们优化了呋喃部分,该部分被认为可能与药物引起的肝损伤相关。代表性抑制剂N14,4- (2-(二甲氨基)乙基)-N - ((1,2,3,5,6,7-六氢-s -indacen-4-yl)氨基甲酰基)苯磺酰胺,不仅保持了MCC950 的 NLRP3 抑制活性,IC 50为 25 nM,而且在人肝细胞系和小鼠原代肝细胞中也显示出改善的耐受性。此外,N14还表现出优异的药代动力学特性,口服生物利用度为 85.2%。体内研究表明,N14在多种 NLRP3 相关动物模型疾病中比 MCC950 更有效,包括非酒精性脂肪性肝炎、致命性感染性休克和结肠炎。我们的研究提供了一种直接靶向 NLRP3 炎性体的先导化合物,可开发为 NLRP3 驱动疾病的新型治疗候选药物。
更新日期:2023-09-11
中文翻译:
新型磺酰脲基 NLRP3 炎症小体抑制剂可有效治疗非酒精性脂肪性肝炎、内毒素性休克和结肠炎
NLRP3 炎症小体是先天免疫的重要组成部分,参与各种炎症性疾病的病理生理学。在本研究中,我们基于MCC950设计并合成了一系列NLRP3炎症小体抑制剂。具体来说,我们优化了呋喃部分,该部分被认为可能与药物引起的肝损伤相关。代表性抑制剂N14,4- (2-(二甲氨基)乙基)-N - ((1,2,3,5,6,7-六氢-s -indacen-4-yl)氨基甲酰基)苯磺酰胺,不仅保持了MCC950 的 NLRP3 抑制活性,IC 50为 25 nM,而且在人肝细胞系和小鼠原代肝细胞中也显示出改善的耐受性。此外,N14还表现出优异的药代动力学特性,口服生物利用度为 85.2%。体内研究表明,N14在多种 NLRP3 相关动物模型疾病中比 MCC950 更有效,包括非酒精性脂肪性肝炎、致命性感染性休克和结肠炎。我们的研究提供了一种直接靶向 NLRP3 炎性体的先导化合物,可开发为 NLRP3 驱动疾病的新型治疗候选药物。