Title:Substituted 4H-3,1-benzoxazine-4-one Derivatives as Inhibitors of Cathepsin G
Volume: 20
Issue: 10
Author(s): Kholoud F. Aliter and Rami A. Al-Horani*
Affiliation:
- Division of Basic
Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans LA 70125, USA
Keywords:
Cathepsin G, a serine protease, 4H-3, 1-benzoxazine-4-one, inflammation, CatG inhibitors, serine proteases, trypsin.
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 IC50 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.
