Synthetic inhibitors of serine proteinases. 34. The effect of modification of the amidino function of N-alpha-substituted 4-amidinophenylalanine amides on inhibitory activity

Cyclic amides of N alpha-arylsulfonylated 4-amidinophenylalanine are selective inhibitors of thrombin. The exchange of the amidino function for an aminomethyl residue does not influence the selectivity and potency of their inhibitory activity. In contrast, the modification of the amidino function of the N alpha-arylsulfonylaminoacylated compound N alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide results in a drastic loss of inhibitory activity. Only the oxamidino derivative possesses considerable high affinity for thrombin. Obviously, in tight binding inhibitors of thrombin structural variation results in any case in a loss of inhibitory activity.     

Synthetic inhibitors of serine proteinases. Part 24: Inhibition of trypsin, plasmin and thrombin by cyclic amides of N alpha-arylsulfonylamidinophenyl-glycines (author's transl)

Cyclic amides of n alpha-arylsulfonyl (3-amidinophenyl)glycine are potent inhibitors of the serine proteinase trypsin, plasmin and thrombin. The weak inhibitory activity of the corresponding 4-amidinophenylglycine derivatives cannot be explained in terms of the structure-activity relationships established for benzamidine derivatives. It might be caused by steric hindrance of enzyme-inhibitor interactions.     

Synthetic inhibitors of serine proteinases. 31. The inhibition of trypsin, plasmin and thrombin by isomeric compounds of N alpha -arylsulfonylated omega-amidinophenyl-alpha-aminoalkylcarboxylic acid amides

Isomeric compounds of N alpha-arylsulfonylated amides of omega-amidinophenyl-alpha-aminoalkylcarboxylic acids--N alpha-amidinophenylsulfonylated amides or N alpha-arylsulfonylated amidino anilides of omega-phenyl-alpha-aminoalkylcarboxylic acids, respectively--possess weak antithrombin activity as compared to the derivatives of the basic structure. Thus, the assumption is corroborated that specific enzyme-inhibitor interactions account for the high antithrombin activity of certain derivatives of omega-amidinophenyl-alpha-aminoalkylcarboxylic acids. In contrast, amidinoanilides of N alpha-substituted omega-phenyl-alpha-aminoalkylcarboxylic acids are potent inhibitors of trypsin and plasmin, their inhibitory activity approaches that of primary amides of N alpha-substituted omega-amidinophenyl-alpha-aminoalkylcarboxylic acids.     

Synthetic inhibitors of serine proteinases. Part 25: Inhibition of trypsin, plasmin and thrombin by amides of N alpha-substituted amidinophenylalanines and 3-amidinophenyl-3-aminopropionic acids (author's transl)

Amides of N alpha-substituted 3-amidinophenylalanine are potent inhibitors of the serine proteinases trypsin, plasmin and thrombin. They belong to the most potent inhibitors of these enzymes of the benzamidine type. In contrast, amides of 4-amidinophenylalanine possess weak inhibitory activity towards trypsin and plasmin. The cyclic amides of this group, however, are potent thrombin inhibitors. These derivatives are the first benzamidines with specific antithrombin activity. The isomeric compounds of 3-amidinophenyl-3-aminopropionic acids possess weak inhibitory effects on trypsin, plasmin and thrombin.     

Synthetic serine protease inhibitors. 29. Synthesis of alpha-arylsulphonylamino-beta-(4-amidinophenyl)ethyl-chloromethylketones and their inhibitory activity against trypsin, plasmin and thrombin

The synthesis of alpha-arylsulphonylamino-beta-(4-amidinophenyl)ethyl-chloromethylketones, the structures of which correspond largely to those of the antiproteolytically very potent N alpha-arylsulphonylated 4-amidinophenylalaninamides, was realized starting from 4-cyanophenylalanine hydrochloride. After N alpha-arylsulphonylation this compound was converted via the acid chlorides by treatment with diazomethane into alpha-arylsulphonylamino-beta-(4-cyanophenyl)ethyl-diazomethylketones from which the corresponding chloromethylketones were afforded by treatment with concentrated hydrochloric acid. The conversion of the cyano function into the amidine function via the thiocarbamoyl and the thioimidic acid esters yielded the compounds named in the title. The substances produced no irreversible inhibition of the serine proteinases trypsin, plasmin and thrombin. Their competitive inhibitory effect was almost as potent as that of N alpha-arylsulphonylated 4-amidinophenylalanine ethylesters.     

Synthetic inhibitors of serine proteinases. Part 26: Inhibition of trypsin, plasmin and thrombin by amides of N alpha-arylsulfonylated 2-amino-4-(4-amidino-phenyl) butyric acid and 2-amino-5-amidinophenyl valeric acids (author's transl)

Among the derivatives of the N alpha-arylsulfonylated omega-amidinophenyl-alpha-aminoalkyl carboxylic acids, the primary amides of N alpha-arylsulfonylated 2-amino-4-(4-amidinophenyl) butyric acid proved to be compounds with strong antiplasmin and antitrypsin activity, they exert, however, only slight inhibitory effect on thrombin. So far, no benzamidine derivatives with strong inhibitory effects on plasmin but with weak antithrombin activity have been known. The secondary amides of the N alpha-arylsulfonylated 2-amino-4-(4-amidinophenyl)butyric acid possess slight inhibitory effects, the corresponding derivatives of 2-amino-5-amidinophenyl valeric acids, however, are potent inhibitors of thrombin.     

Synthetic inhibitors of serine proteinases. Part 19: On the inhibitory effect of amidinobenzylidene derivatives of benzo-condensed cycloalkanones on trypsin, plasmin and thrombin (author's transl)]

Amidinobenzylidene derivatives of benzo-condensed cycloalkanones proved to be potent competitive inhibitors of thrombin and trypsin. On the contrary, the antiplasmin effect of these derivatives is considerably less marked. The conversion of 3-amidinochalcone to derivatives in which the carbonyl group is incorporated into a ring, does not lead to fundamental changes in the inhibitory effect on trypsin and thrombin, whereas the antiplasmin effect decreases. Compared to 4-amidinochalcone, the 2-(4-amidinobenzylidene) derivatives of indanone-(1) and tetralone-(1) exert a stronger inhibitory effect on trypsin and thrombin. The introduction of a hetero-atom to the cycloalkanone component affected the inhibitory effect on trypsin and thrombin but insignificantly. From these results it is concluded that also in amidinobenzylidene derivatives of benzo-condensed cycloalkanone derivatives, the carbonyl function shares in enzyme-inhibitor binding.