SYNTHESIS AND INHIBITING PROPERTIES TOWARD TRYPSIN LIKE PROTEASES OF N-ALPHA-(N,N-DIMETHYLCARBAMOYL)-ALPHA-AZAORNITINE AND N-ALPHA-(N,N-DIMETHYLCARBAMOYL)-ALPHA-AZALYSINE ESTERS

N(alpha)-(N,N-dimethylcarbamoyl)-alpha-azaornitine and N(alpha)-(N,N-dimethylcarbamoyl)-alpha-azalysine phenyl and p-nitrophenyl esters (7-10) were synthesized and tested as inhibitors of trypsin, chymotrypsin and thrombin. The N,N-dimethylcarbamoyl group was chosen to decrease the tendency of acylcarbazates to cyclization into 1,3,4-oxadiazol-2(3H)-ones. Only the p-nitrophenyl alpha-azaornithine derivative 8 was inactivated rapidly by intramolecular acylation of the terminal amino group, rather than by cyclization to oxadiazolone, in aqueous solution at pH 8. The corresponding alpha-azalysine derivative 10 is completely unaffected under the same conditions. Rapid inactivation of thrombin and trypsin only was observed for all alpha-azapeptide esters 7-10 at 0.5 mM inhibitor concentration. No proteolytic activity was restored after 24 h following 2000 fold dilution of the inhibitor concentration suggesting formation of very stable acylenzymes.