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Volume 20, Issue 10
  • ISSN: 1573-4064
  • E-ISSN: 1875-6638

Abstract

Background

Cathepsin G (CatG) is a cationic serine protease with a wide substrate specificity. CatG has been reported to play a role in several pathologies, including rheumatoid arthritis, ischemic reperfusion injury, acute respiratory distress syndrome, and cystic fibrosis, among others.

Objective

We aim to develop a new class of CatG inhibitors and evaluate their potency and selectivity against a series of serine proteases.

Methods

We exploited chemical synthesis as well as chromogenic substrate hydrolysis assays to construct and evaluate the new inhibitors.

Results

In this communication, we report on a new class of CatG inhibitors of 4H-3,1-benzoxazin-4-one derivatives. We constructed a small library of seven substituted 4H-3,1-benzoxazin-4-one derivatives and identified their inhibition potential against CatG. Five molecules were identified as CatG inhibitors with values of 0.84-5.5 µM. Inhibitor 2 was the most potent, with an IC of 0.84 ± 0.11 µM and significant selectivity over representative serine proteases of thrombin, factor XIa, factor XIIa, and kallikrein.

Conclusion

Thus, we propose this inhibitor as a lead molecule to guide subsequent efforts to develop clinically relevant potent and selective CatG inhibitors for use as anti-inflammatory agents.

© 2024 Bentham Science Publishers
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/content/journals/mc/10.2174/0115734064300678240408084822
2024-12-01
2025-02-17

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/content/journals/mc/10.2174/0115734064300678240408084822
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Substituted 4H-3,1-benzoxazine-4-one Derivatives as Inhibitors of Cathepsin G
Med. Chem. 20, 944 (2024); https://doi.org/10.2174/0115734064300678240408084822
/content/journals/mc/10.2174/0115734064300678240408084822
/content/journals/mc/10.2174/0115734064300678240408084822
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  • Article Type:     Research Article
Keyword(s): 4H-3,1-benzoxazine-4-one; a serine protease; CatG inhibitors; Cathepsin G; inflammation; serine proteases; trypsin

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