2. Academic Validation
  3. Discovery of Novel 2,3-Dihydro-1 H-indene-5-sulfonamide NLRP3 Inflammasome Inhibitors Targeting Colon as a Potential Therapy for Colitis

Discovery of Novel 2,3-Dihydro-1 H-indene-5-sulfonamide NLRP3 Inflammasome Inhibitors Targeting Colon as a Potential Therapy for Colitis

  • J Med Chem. 2023 Dec 14;66(23):16141-16167. doi: 10.1021/acs.jmedchem.3c01511.
Simin Sun 1,  Zhuoyue Li 1 2,  Chao Huang 1,  Jinyu Liu 1,  Qixin Yu 3,  Xiaolin Jiang 1 2,  Kairui Yue 1,  Jianchun Zhao 1,  Tongqiang Xu 3,  Yankai Liu 1,  Xiaoyang Li 1 2 3,  Chong Qin 1 2 3,  Yuqi Jiang 1 2 3
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
  • 2 Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China.
  • 3 Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, P.R. China.
PMID: 38029358 DOI: 10.1021/acs.jmedchem.3c01511
Abstract

The NLRP3 inflammasome is a multiprotein complex that plays a crucial role in the pathophysiology of multiple inflammation-related diseases. In this study, we designed and synthesized a series of novel 2,3-dihydro-1H-indene-5-sulfonamide analogues as NLRP3 inflammasome inhibitors, and then identified compound 15z as a potent and specific inhibitor (IC50: 0.13 μM) with low toxicity. Mechanistic studies indicate that 15z binds directly to NLRP3 protein (KD: 102.7 nM), blocking the assembly and activation of the NLRP3 inflammasome and effectively inhibiting cell Pyroptosis. Given the notable distribution of 15z in the colon, the DSS-induced colitis model was employed to evaluate its in vivo effectiveness. 15z significantly impacted NLRP3 inflammasome activation and relieved inflammatory bowel disease symptoms in this model. Acute and subacute toxicity studies suggested that 15z has a favorable safety profile. Our results indicate that 15z has great potential to be further developed as a candidate for the treatment of inflammatory bowel disease.

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