2. Academic Validation
  3. Discovery and In Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor

Discovery and In Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor

  • J Med Chem. 2021 Aug 26;64(16):11857-11885. doi: 10.1021/acs.jmedchem.1c00104.
Xing Chen 1,  Yaoyao Yan 1,  Zhaoyan Zhang 1,  Faming Zhang 1,  Mingming Liu 1,  Leran Du 1,  Haixia Zhang 1,  Xiaobao Shen 1,  Dahai Zhao 2,  Jing Bo Shi 1,  Xinhua Liu 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, P. R. China.
  • 2 Affiliated Hospital 2, Anhui Medical University, Hefei 230601, P. R. China.
PMID: 34374541 DOI: 10.1021/acs.jmedchem.1c00104
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 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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