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

Sun, Simin; Li, Zhuoyue; Huang, Chao; Liu, Jinyu; Yu, Qixin; Jiang, Xiaolin; Yue, Kairui; Zhao, Jianchun; Xu, Tongqiang; Liu, Yankai; Li, Xiaoyang; Qin, Chong; Jiang, Yuqi

doi:10.1021/acs.jmedchem.3c01511

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J. Med. Chem.

2023

DOI: 10.1021/acs.jmedchem.3c01511

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

Simin Sun,

Zhuoyue Li,

Chao Huang

et al.

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2024

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Cited by 4 publications

References 53 publications

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Discovery of novel biphenyl-sulfonamide analogues as NLRP3 inflammasome inhibitors

Huang,

Liu,

Chen

et al. 2024

Bioorganic Chemistry

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Discovery of novel biphenyl-sulfonamide analogues as NLRP3 inflammasome inhibitors

Huang,

Liu,

Chen

et al. 2024

Bioorganic Chemistry

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Design, synthesis and biological evaluation of novel diphenylamine analogues as NLRP3 inflammasome inhibitors

Kang,

Sun,

Wang

et al. 2024

Bioorganic & Medicinal Chemistry

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Design, Synthesis, and Bioevaluation of Novel NLRP3 Inhibitor with IBD Immunotherapy from the Virtual Screen

Zhang,

Wu,

Yin

et al. 2024

J. Med. Chem.

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NLRP3, a crucial member of the NLRP family, plays a pivotal role in immune regulation and inflammatory modulation. Here, we report a potent and specific NLRP3 inhibitor Z48 obtained though docking-based virtual screening and structure−activity relationship studies with an IC 50 of 0.26 μM in THP-1 cells and 0.21 μM in mouse bone marrow-derived macrophages. Mechanistic studies indicated that Z48 could bind directly to the NLRP3 protein (K D = 1.05 μM), effectively blocking the assembly and activation of the NLRP3 inflammasome, consequently manifesting anti-inflammatory properties. Crucially, with acceptable mouse pharmacokinetic profiles, Z48 demonstrated notable therapeutic efficacy in a mouse model of DSSinduced ulcerative colitis, while displaying no significant therapeutic impact on NLRP3 KO mice. In conclusion, this study provided a promising NLRP3 inflammasome inhibitor with novel molecular scaffold, poised for further development as a therapeutic candidate in the treatment of inflammatory bowel disease.

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

Cited by 4 publications

References 53 publications

Discovery of novel biphenyl-sulfonamide analogues as NLRP3 inflammasome inhibitors

Discovery of novel biphenyl-sulfonamide analogues as NLRP3 inflammasome inhibitors

Design, synthesis and biological evaluation of novel diphenylamine analogues as NLRP3 inflammasome inhibitors

Design, Synthesis, and Bioevaluation of Novel NLRP3 Inhibitor with IBD Immunotherapy from the Virtual Screen

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