Studies on 2-benzyloxy-4H-3,1-benzoxazin-4-ones as serine protease inhibitors.
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.
Institut für Pharmazie, Universität Leipzig, Germany. guetscho@uni-leipzig.de
M
M
Gütschow
U
U
Neumann
J
J
Sieler
K
K
Eger
D048588:Benzoxazines; D018360:Crystallography, X-Ray; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D007962:Leukocytes / Q000201:enzymology; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
C114299:2-benzyloxy-4H-3,1-benzoxazin-4-one; C114301:2-benzyloxy-5-methyl-4H-3,1-benzoxazin-4-one; C114300:2-benzyloxy-6-methyl-4H-3,1-benzoxazin-4-one; D048588:Benzoxazines; D010078:Oxazines; D015842:Serine Proteinase Inhibitors; D019272:Leukocyte Elastase