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.

中文翻译：

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作为组织蛋白酶 G 抑制剂的取代 4H-3,1-苯并恶嗪-4-酮衍生物


背景：组织蛋白酶 G (CatG) 是一种具有广泛底物特异性的阳离子丝氨酸蛋白酶。据报道，CatG 在多种病理学中发挥作用，包括类风湿性关节炎、缺血性再灌注损伤、急性呼吸窘迫综合征和囊性纤维化等。目的：我们的目标是开发一类新型 CatG 抑制剂，并评估其针对一系列丝氨酸蛋白酶的效力和选择性。方法：我们利用化学合成以及显色底物水解测定来构建和评估新的抑制剂。结果：在本次通讯中，我们报告了一类新型 4H-3,1-苯并恶嗪-4-酮衍生物的 CatG 抑制剂。我们构建了一个由 7 种取代的 4H-3,1-苯并恶嗪-4-酮衍生物组成的小型文库，并鉴定了它们对 CatG 的抑制潜力。五个分子被鉴定为 CatG 抑制剂，其浓度范围为 0.84-5.5 μM。抑制剂 2 是最有效的，IC50 为 0.84 ± 0.11 μM，并且比凝血酶、因子 XIa、因子 XIIa 和激肽释放酶的代表性丝氨酸蛋白酶具有显着选择性。结论：因此，我们建议将该抑制剂作为先导分子，以指导后续努力开发临床相关的有效且选择性的 CatG 抑制剂，用作抗炎剂。