2. Academic Validation
  3. Design, synthesis and biological evaluation of sulfonylurea derivatives as NLRP3 inflammasome inhibitors

Design, synthesis and biological evaluation of sulfonylurea derivatives as NLRP3 inflammasome inhibitors

  • Bioorg Med Chem Lett. 2024 Oct 10:114:129987. doi: 10.1016/j.bmcl.2024.129987.
Haonan Feng 1,  Donglai Li 2,  Fuli Zhu 1,  Caihong Jiang 2,  Mengjun Su 1,  Yichao Kong 2,  Yonghao Zheng 1,  Yaxia Yuan 3,  Weiwei Huang 4,  Xiabin Chen 5,  Lei Ma 6
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
  • 2 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
  • 3 Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, TX 78229, USA.
  • 4 Hangzhou Matrix Biopharmaceutical Co., Ltd, Hangzhou, Zhejiang 311121, China. Electronic address: 1332532220@qq.com.
  • 5 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. Electronic address: xch226@hznu.edu.cn.
  • 6 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address: malei@ecust.edu.cn.
PMID: 39395633 DOI: 10.1016/j.bmcl.2024.129987
Abstract

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.

Keywords

NLRP3 inflammasome; Small molecule inhibitors; Structural modification; Sulfonylurea derivatives.

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