化学
部分
苯甲酰胺
体内
磺胺
炎症体
组合化学
铅化合物
化学合成
结构-活动关系
体外
生物活性
立体化学
药理学
生物化学
受体
生物技术
生物
医学
作者
Jacob Fulp,He Li,Stefano Toldo,Yuqi Jiang,Ashley Boice,Chunqing Guo,Xia Li,Andrew Rolfe,Dong Sun,Antonio Abbate,Xiangyang Wang,Shijun Zhang
标识
DOI:10.1021/acs.jmedchem.8b00733
摘要
NLRP3 inflammasome plays critical roles in a variety of human diseases and represents a promising drug target. In this study, we established the in vivo functional activities of JC124, a previously identified NLRP3 inflammasome inhibitor from our group, in mouse models of Alzheimer’s disease and acute myocardial infarction. To understand the chemical space of this lead structure, a series of analogues were designed, synthesized, and biologically characterized. The results revealed the critical roles of the two substituents on the benzamide moiety of JC124. On the other hand, modifications on the sulfonamide moiety of JC124 are well tolerated. Two new lead compounds, 14 and 17, were identified with improved inhibitory potency (IC50 values of 0.55 ± 0.091 and 0.42 ± 0.080 μM, respectively). Further characterization confirmed their selectivity and in vivo target engagement. Collectively, the results strongly encourage further development of more potent analogues based on this chemical scaffold.
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