Author: Li, Xiaoyang ; Yu, Xinyue ; Jiang, Yuqi ; Yang, Zixuan ; Jiang, Xiaolin ; Qin, Chong ; Ma, Shumin ; Lu, Penghui ; Li, Zhuoyue ; Wang, Chengli ; Chen, Yiming ; Zhang, Siqi ; Li, Zhimin ; Tai, Zhengfu ; Du, Shanshan

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.

Journal of Medicinal Chemistry

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

Author: Qin, Chong ; Zhang, Siqi ; Yang, Zixuan ; Li, Xiaoyang ; Lu, Penghui ; Ma, Shumin ; Wang, Chengli ; Li, Zhimin ; Li, Zhuoyue ; Jiang, Yuqi ; Chen, Yiming ; Yu, Xinyue ; Du, Shanshan ; Jiang, Xiaolin ; Tai, Zhengfu

The NLRP3 inflammasome is a critical component of innate immunity involved in the pathophysiol. 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.

100 Deals associated with N-14(Ocean University of China)

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Indication	Highest Phase	Country/Location	Organization	Date
Colitis	Preclinical	China	Ocean University of China	11 Sep 2023
Nonalcoholic Steatohepatitis	Preclinical	China	Ocean University of China	11 Sep 2023
Shock, Septic	Preclinical	China	Ocean University of China	11 Sep 2023

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