Gütschow M, Neumann U, Sieler J, Eger K
Institut für Pharmazie, Universität Leipzig, Germany.
Pharm Acta Helv. 1998 Jul;73(2):95-103. doi: 10.1016/s0031-6865(98)00003-x.
The class of 3,1-benzoxazin-4-ones includes potent inhibitors of various serine proteases. Structural investigation on three 2-benzyloxy-4H-3,1-benzoxazin-4-ones (1-3) are described with respect to their reactivity to alkaline hydrolysis. The 13C NMR data of 2-benzyloxy-5-methyl-4H-3,1-benzoxazin-4-one 3 are discussed. This peri substituted compound was subjected to a crystal structure analysis. The heterocyclic skeleton together with the carbonyl oxygen and the methyl carbon is planar, and only small angle distortions occurred. The inhibition of neutrophil serine proteases by 1-3 is reported. The different reactivity of the 5-methyl derivative 3 towards serine proteases is mainly influenced by specific interactions within the active sites. Thus, 3 was found to rapidly acylate human leukocyte proteinase 3 and exhibited a Ki value of 1.8 nM.
3,1-苯并恶嗪-4-酮类包括多种丝氨酸蛋白酶的强效抑制剂。描述了三种2-苄氧基-4H-3,1-苯并恶嗪-4-酮（1-3）对碱性水解反应性的结构研究。讨论了2-苄氧基-5-甲基-4H-3,1-苯并恶嗪-4-酮3的13C NMR数据。对该周位取代化合物进行了晶体结构分析。杂环骨架与羰基氧和甲基碳是平面的，仅发生小角度扭曲。报道了1-3对中性粒细胞丝氨酸蛋白酶的抑制作用。5-甲基衍生物3对丝氨酸蛋白酶的不同反应性主要受活性位点内特定相互作用的影响。因此，发现3能快速酰化人白细胞蛋白酶3，其Ki值为1.8 nM。
