Structure-Activity Relationships for the Inhibition of Plasmin and Plasminogen Activation by Aromatic Diamidines and a Study of the Effect of Plasma Proteins on the Inhibition Process

Summary

1. Structure-activity relationships for the inhibition of human plasmin were established for a large series of aromatic diamidines. The compounds are reversible competitive inhibitors and block the amidase and fibrinolytic activities of the enzym. The results confirm pentamidine (4,4’-diamidino α ω-diphenoxy-pentane) as the leading inhibitor (Ki = 3.3 (μM) and show distinct differences in the inhibitory spectrum of diamidines against plasmin as compared with trypsin, pancreatic kallikrein and thrombin.

2. Diamidines are potent inhibitors of the SK-dependent activation of human plasminogen and of the activation of bovine plasminogen by the SK-human plasmin activator complex. Pentamidine is again the most powerful inhibitor of these systems.

3. In fibrinolytic assays of plasmin and in plasminogen activation tests the relative strength of diamidines as compared with E-ACA is greatly influenced by the test conditions. The decisive factor is the presence in the incubation mixtures of lesser or greater amounts of plasma or serum proteins which bring about a fall in the absolute strength of diamidines and an increase in the absolute strength of E-ACA. In the fibrinolytic assay of plasmin, this modifying effect of added serum is based on a time- dependent interaction with the enzyme, thereby presumably altering its susceptibility to inhibition.

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