Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 16, Pages 11857-11885Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00104
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Funding
- Natural Science Foundation of China [21977001]
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The study details the discovery process of a potent non-peptidyl non-covalent cathepsin C inhibitor, highlighting structure-based optimization and structure-activity relationship studies. The lead compound showed strong anti-inflammatory activity in an animal model, validating the potential of non-peptidyl and non-covalent derivatives as effective cathepsin C inhibitors and prompting further drug discovery efforts.
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.
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