title: Inhibition of cathepsin G by 4H-3,1-benzoxazin-4-ones.
abstract: A series of 4H-3,1-benzoxazin-4-ones is reported that inhibit the serine proteases human cathepsin G and bovine chymotrypsin. The synthesis and kinetic parameters of the alkaline hydrolysis is described. These compounds act as acyl-enzyme inhibitors of both enzymes. The reaction of cathepsin G with 2-benzylamino-4H-3,1-benzoxazin-4-one (20) was studied in detail. A partition in deacylation of the initially formed acyl-enzyme was observed, leading to the formation of 2-(3-benzylureido)benzoic acid (26) and 3-benzylquinazoline-2,4-(1H,3H)-dione (27). A 6-methyl substitution strongly increased the acylation rate of both proteases. Introduction of an aryl moiety into the 2-substituent led to compounds with Ki values towards cathepsin G in the nanomolar range. Their inhibitory potency is stronger than that of other synthetic inhibitors of cathepsin G.
authors.affiliation: Institute of Pharmacy, University of Leipzig, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gütschow
authors.forename: U
authors.initials: U
authors.lastname: Neumann
mesh_terms: D000818:Animals; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002417:Cattle; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D010078:Oxazines; D015842:Serine Proteinase Inhibitors; D002403:Cathepsins; D012697:Serine Endopeptidases; D002918:Chymotrypsin; C534094:CTSG protein, human; D056649:Cathepsin G