2. Academic Validation
  3. Novel Sulfonylurea-Based NLRP3 Inflammasome Inhibitor for Efficient Treatment of Nonalcoholic Steatohepatitis, Endotoxic Shock, and Colitis

Novel Sulfonylurea-Based NLRP3 Inflammasome Inhibitor for Efficient Treatment of Nonalcoholic Steatohepatitis, Endotoxic Shock, and Colitis

  • J Med Chem. 2023 Sep 28;66(18):12966-12989. doi: 10.1021/acs.jmedchem.3c00894.
Zhuoyue Li 1 2,  Yiming Chen 1,  Xiaolin Jiang 1 3,  Penghui Lu 1,  Chengli Wang 2,  Zhimin Li 2,  Xinyue Yu 2,  Zixuan Yang 1,  Shumin Ma 1 2,  Shanshan Du 3,  Zhengfu Tai 2,  Xiaoyang Li 1 2,  Siqi Zhang 1 2,  Yuqi Jiang 1 2,  Chong Qin 1 2 4
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 2 Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China.
  • 3 College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China.
  • 4 Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China.
PMID: 37695288 DOI: 10.1021/acs.jmedchem.3c00894
Abstract

The NLRP3 inflammasome is a critical component of innate immunity involved in the pathophysiology of various inflammatory diseases. In this study, we designed and synthesized a series of NLRP3 inflammasome inhibitors based on MCC950. Specifically, we optimized the furan moiety, which is considered to be potentially associated with drug-induced liver injury. The representative inhibitor N14, 4-(2-(dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonamide, not only maintains the NLRP3 inhibitory activity of MCC950 with IC50 of 25 nM but also demonstrates improved tolerability in human hepatic cells line and mouse primary hepatocytes. In addition, N14 exhibits superior pharmacokinetic properties, with an oral bioavailability of 85.2%. In vivo studies demonstrate that N14 is more effective than MCC950 in multiple NLRP3-related animal model diseases, including nonalcoholic steatohepatitis, lethal septic shock, and colitis. Our research has provided a lead compound that directly targets the NLRP3 inflammasome and can be developed as a novel therapeutic candidate for NLRP3-driven diseases.

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