TY - JOUR
T1 - Design, synthesis and biological evaluation of sulfonylurea derivatives as NLRP3 inflammasome inhibitors
AU - Feng, Haonan
AU - Li, Donglai
AU - Zhu, Fuli
AU - Jiang, Caihong
AU - Su, Mengjun
AU - Kong, Yichao
AU - Zheng, Yonghao
AU - Yuan, Yaxia
AU - Huang, Weiwei
AU - Chen, Xiabin
AU - Ma, Lei
N1 - Publisher Copyright:
© 2024 Elsevier Ltd
PY - 2024/12/1
Y1 - 2024/12/1
N2 - The NLRP3 inflammasome has been extensively studied in recent years and its aberrant activation can exacerbate inflammatory responses, contributing to various diseases. MCC950, a sulfonylurea drug, is a potent selective inhibitor of the NLRP3 inflammasome. However, its clinical development was halted due to hepatotoxicity, and studies have indicated significant reduction in activity among its metabolites. Building upon MCC950, we referenced substitution sites of NP3-146 for structural modifications aimed at addressing potential metabolism-related issues. Consequently, we synthesized a series of sulfonylurea derivatives. Ultimately, the optimized compound C4 exhibited a remarkable 80.39 % inhibition of IL-1β at 2 μM, with an IC50 value of 0.805 μM. In conclusion, compound C4 shows potential as a lead compound and warrants further development as an anti-inflammatory NLRP3 inhibitor.
AB - The NLRP3 inflammasome has been extensively studied in recent years and its aberrant activation can exacerbate inflammatory responses, contributing to various diseases. MCC950, a sulfonylurea drug, is a potent selective inhibitor of the NLRP3 inflammasome. However, its clinical development was halted due to hepatotoxicity, and studies have indicated significant reduction in activity among its metabolites. Building upon MCC950, we referenced substitution sites of NP3-146 for structural modifications aimed at addressing potential metabolism-related issues. Consequently, we synthesized a series of sulfonylurea derivatives. Ultimately, the optimized compound C4 exhibited a remarkable 80.39 % inhibition of IL-1β at 2 μM, with an IC50 value of 0.805 μM. In conclusion, compound C4 shows potential as a lead compound and warrants further development as an anti-inflammatory NLRP3 inhibitor.
KW - NLRP3 inflammasome
KW - Small molecule inhibitors
KW - Structural modification
KW - Sulfonylurea derivatives
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U2 - 10.1016/j.bmcl.2024.129987
DO - 10.1016/j.bmcl.2024.129987
M3 - Article
C2 - 39395633
AN - SCOPUS:85206890135
SN - 0960-894X
VL - 114
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
M1 - 129987
ER -