Inhibition of cathepsin G by 4H-3,1-benzoxazin-4-ones

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 K-i values towards cathepsin G in the nanomolar range. Their inhibitory potency is stronger than that of other synthetic inhibitors of cathepsin G. (C) 1997 Elsevier Science Ltd.