A series of 4H-3,1-benzoxazin-4-ones is reported that inhibit the seri
ne 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 stu
died in detail. A partition in deacylation of the initially formed acy
l-enzyme was observed, leading to the formation of 2-(3-benzylureido)b
enzoic acid (26) and 3-benzylquinazoline-2,4-(1H,3H)-dione (27). A 6-m
ethyl substitution strongly increased the acylation rate of both prote
ases. Introduction of an aryl moiety into the 2-substituent led to com
pounds with K-i values towards cathepsin G in the nanomolar range. The
ir inhibitory potency is stronger than that of other synthetic inhibit
ors of cathepsin G. (C) 1997 Elsevier Science Ltd.