1. Discovery and In Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor.
- Author
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Chen X, Yan Y, Zhang Z, Zhang F, Liu M, Du L, Zhang H, Shen X, Zhao D, Shi JB, and Liu X
- Subjects
- Animals, Anti-Inflammatory Agents chemical synthesis, Anti-Inflammatory Agents metabolism, Anti-Inflammatory Agents toxicity, Cathepsin C metabolism, Cell Line, Tumor, Drug Discovery, Humans, Inflammation etiology, Inflammation pathology, Lung drug effects, Lung pathology, Male, Mice, Inbred ICR, Microsomes, Liver metabolism, Molecular Docking Simulation, Molecular Structure, Protease Inhibitors chemical synthesis, Protease Inhibitors metabolism, Protease Inhibitors toxicity, Protein Binding, Pulmonary Disease, Chronic Obstructive complications, Pulmonary Disease, Chronic Obstructive pathology, Pyrimidines chemical synthesis, Pyrimidines metabolism, Pyrimidines toxicity, Rats, Sprague-Dawley, Structure-Activity Relationship, Mice, Rats, Anti-Inflammatory Agents therapeutic use, Cathepsin C antagonists & inhibitors, Inflammation drug therapy, Protease Inhibitors therapeutic use, Pulmonary Disease, Chronic Obstructive drug therapy, Pyrimidines therapeutic use
- Abstract
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 IC
50 = 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.- Published
- 2021
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