- Discovery and in Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor
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Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent "non-peptidyl non-covalent cathepsin C inhibitor"was described with hit finding, structure optimization, and lead discovery. Starting with hit 14, structure-based optimization and structure-activity relationship study were comprehensively carried out, and lead compound 54 was discovered as a potent drug-like cathepsin C inhibitor both in vivo and in vitro. Also, compound 54 (with cathepsin C Enz IC50 = 57.4 nM) exhibited effective anti-inflammatory activity in an animal model of chronic obstructive pulmonary disease. These results confirmed that the non-peptidyl and non-covalent derivative could be used as an effective cathepsin C inhibitor and encouraged us to continue further drug discovery on the basis of this finding.
- Chen, Xing,Yan, Yaoyao,Zhang, Zhaoyan,Zhang, Faming,Liu, Mingming,Du, Leran,Zhang, Haixia,Shen, Xiaobao,Zhao, Dahai,Shi, Jing Bo,Liu, Xinhua
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p. 11857 - 11885
(2021/09/02)
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- False positives in a reporter gene assay: Identification and synthesis of substituted N-pyridin-2-ylbenzamides as competitive inhibitors of firefly luciferase
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Luciferase reporter-gene assays are a commonly used technique in high-throughput screening campaigns. In this study, we report on a luciferase inhibitor (1), which emerged from an antagonistic G protein-coupled receptor luciferase reporter-gene assay scre
- Heitman, Laura H.,Van Veldhoven, Jacobus P. D.,Zweemer, Annelien M.,Ye, Kai,Brussee, Johannes,Ijzerrnan, Adriaan P.
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supporting information; experimental part
p. 4724 - 4729
(2009/06/18)
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