Synthetic Inhibitors of Trypsin, Plasmin and Chymotrypsin

Abstract

4-Aminobutyl and 6-aminohexyl butyrate, and hexyl N'-benzoyl-D-lysinate were prepared, and their inhibitory effects on trypsin [EG 3.4.4.4] and plasmin [EC 3.4.4.14] were examined. The inhibitory effects of various derivatives of L-phenylalanine and β-phenylpropionic acid on chymotryptic [EG 3.4.4.5] activity were also examined. No inhibitory effect on the caseinolytic and esterolytic activities of trypsin was observed with 4-aminobutyl or 6-aminohexyl butyrate, and these compounds were insensitive to trypsin. Hexyl N'-benzoyl-D-lysinate inhibited, though less than hexyl s-amino-caproate, the caseinolytic and esterolytic activities of trypsin and plasmin, and was hydrolyzed slower by trypsin than the latter. β-Phenylpropionic acid, β-phenylpropionamide and carbobenzo-xyglycine strongly inhibited the esterolytic activity of chymotrypsin, but had little effect on caseinolysis. On the other hand, carbobenzoxy-L-phenylalanine strongly inhibited both esterolysis and caseinolysis. The inhibitory effect of jS-phenylpropionic acid on esterolysis was reduced in the presence of a protein such as casein and albumin. Therefore, β-phenylpropionic acid does not seem to be a competitive inhibitor which combines with the active site of chymotrypsin. However, the inhibitory effect of carbobenzoxy-L-phenylalanine was not reduced in the presence of albumin. 2-Aminoethyl and 6-aminohexyl β-phenylpropionate extensively inhibited both the caseinolytic and esterolytic activities of chymotrypsin, the inhibitory effects of the latter being the stronger. The optical rotation of chymotrypsin was measured between 300 and 500 mμ at 20° in the presence and absence of 6-aminohexyl βphenylpropionate. No difference between the two curves was observed. These results are discussed on the basis of the “ three-point theory”.