Discovery of Novel Pterostilbene-Based Derivatives as Potent and Orally Active NLRP3 Inflammasome Inhibitors with Inflammatory Activity for Colitis

• Published in: Journal of medicinal chemistry 2021-09, Vol.64 (18), p.13633-13657
• Main Authors: Chen, Liu Zeng, Zhang, Xing Xing, Liu, Ming Ming, Wu, Jing, Ma, Duo, Diao, Liang Zhuo, Li, Qingshan, Huang, Yan Shuang, Zhang, Rui, Ruan, Ban Feng, Liu, Xin Hua
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - therapeutic use; Anti-Inflammatory Agents - toxicity; Cell Line; Colitis - chemically induced; Colitis - drug therapy; Dextran Sulfate; Female; Humans; Inflammasomes - antagonists & inhibitors; Interleukin-1beta - antagonists & inhibitors; Macrophages - drug effects; Male; Mice; Mice, Inbred C57BL; Molecular Structure; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; Pyroptosis - drug effects; Stilbenes - chemical synthesis; Stilbenes - therapeutic use; Stilbenes - toxicity; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01007

Studies have shown that the abnormal activation of the NLRP3 inflammasome is involved in a variety of inflammatory-based diseases. In this study, a high content screening model targeting the activation of inflammasome was first established and pterostilbene was discovered as the active scaffold. Based on this finding, total of 50 pterostilbene derivatives were then designed and synthesized. Among them, compound 47 was found to be the best one for inhibiting cell pyroptosis [inhibitory rate (IR) = 73.09% at 10 μM], showing low toxicity and high efficiency [against interleukin-1β (IL-1β): half-maximal inhibitory concentration (IC50) = 0.56 μM]. Further studies showed that compound 47 affected the assembly of the NLRP3 inflammasomes by targeting NLRP3. The in vivo biological activity showed that this compound significantly alleviated dextran sodium sulfate (DSS)-induced colitis in mice. In general, our study provided a novel lead compound directly targeting the NLRP3 protein, which is worthy of further research and structural optimization.