Discovery of Potent, Specific, and Orally Available NLRP3 Inflammasome Inhibitors Based on Pyridazine Scaffolds for the Treatment of Septic Shock and Peritonitis

  • J Med Chem. 2024 Sep 12;67(17):15711-15737. doi: 10.1021/acs.jmedchem.4c01341.
Zhiyuan Fu  1 ,  Yangqin Duan  1 ,  Heying Pei  1 ,  Yurong Zou  1 ,  Minghai Tang  1 ,  Yong Chen  2 ,  Tao Yang  1 ,  Ziyan Ma  1 ,  Wei Yan  1 ,  Kaiyue Su  1 ,  Xiaoying Cai  1 ,  Tao Guo  1 ,  Yaxin Teng  1 ,  Tao Jia  3 ,  Lijuan Chen  1  3
Affiliations
  • 1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2. Innovation Center of Nursing Research and Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China.
  • 3. Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China.
PMID: 39169676 DOI: 10.1021/acs.jmedchem.4c01341
Abstract

The NLRP3 inflammasome is a multiprotein complex that is a component of the innate immune system, involved in the production of pro-inflammatory cytokines. Its abnormal activation is associated with many inflammatory diseases. In this study, we designed and synthesized a series of NLRP3 inflammasome inhibitors based on pyridazine scaffolds. Among them, P33 exhibited significant inhibitory effects against nigericin-induced IL-1β release in THP-1 cells, BMDMs, and PBMCs, with IC50 values of 2.7, 15.3, and 2.9 nM, respectively. Mechanism studies indicated that P33 directly binds to NLRP3 protein (KD = 17.5 nM), inhibiting NLRP3 inflammasome activation and Pyroptosis by suppressing ASC oligomerization during NLRP3 assembly. Additionally, P33 displayed excellent pharmacokinetic properties, with an oral bioavailability of 62%. In vivo efficacy studies revealed that P33 significantly ameliorated LPS-induced septic shock and MSU crystal-induced peritonitis in mice. These results indicate that P33 has great potential for further development as a candidate for treating NLRP3 inflammasome-mediated diseases.

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