Discovery of Triazinone Derivatives as Novel, Specific, and Direct NLRP3 Inflammasome Inhibitors for the Treatment of DSS-Induced Ulcerative Colitis

  • J Med Chem. 2023 Oct 12;66(19):13428-13451. doi: 10.1021/acs.jmedchem.3c00696.
Na Li  1 ,  Xueqin Jiang  1 ,  Ruijia Zhang  1 ,  Neng Ye  1 ,  Minghai Tang  1 ,  Xiaoying Cai  1 ,  Kaiyue Su  1 ,  Jing Peng  1 ,  Xinlu Zhang  1 ,  Min Zhao  2 ,  Wenshuang Wu  3 ,  Haoyu Ye  1
Affiliations
  • 1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2. Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3. Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 37756547 DOI: 10.1021/acs.jmedchem.3c00696
Abstract

NLRP3 is an intracellular sensor protein that causes inflammasome formation and Pyroptosis in response to a wide range of stimuli. Aberrant activation of NLRP3 inflammasome has been implicated in various chronic inflammatory diseases, making it a promising target for therapeutic intervention. In this work, a series of novel triazinone inhibitors of NLRP3 inflammasome were designed and synthesized. Compound L38 was identified for its excellent activity and acceptable metabolic stability among 41 compounds. Additionally, mechanism studies indicated that L38 inhibited NLRP3 inflammasome activation and Pyroptosis by suppressing gasdermin D cleavage, ASC oligomerization, and NLRP3 inflammasome assembly while leaving mitochondrial ROS production, lysosome damage, and chloride/potassium efflux unaffected. Further investigation revealed that L38 could bind to the NACHT domain to exert inflammatory properties. Importantly, L38 exhibited positive therapeutic effects in DSS-induced ulcerative colitis mouse model. Taken together, this study presents a promising inhibitor of NLRP3 inflammasome deserving further investigation.

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