Inhibitory effect of amidino-substituted heterocyclic compounds on the amidase activity of plasmin and of high and low molecular weight urokinase and on urokinase-induced plasminogen activation
Geratz, J.D.; Shaver, S.R.; Tidwell, R.R.
Thrombosis Research 24(1-2): 73-83
1981
ISSN/ISBN: 0049-3848 PMID: 6460342 Document Number: 182016
A number of heterocyclic mono- and diamidines were examined for their inhibitory effect on urokinase and on plasmin. Interaction with both enzymes was competitive in nature. A comparison of the inhibition constants revealed similarities and differences in the binding conditions between the 2 active sites. The most potent inhibitor in the series was represented by bis (5-amidino-2-benzimidazolyl)methane with Ki values of 2.3 .times. 10-6 and 2.6 .times. 10-6 M for high MW urokinase and plasmin, respectively. The high and low MW forms of urokinase were very similar in their susceptibility to inhibition by amidines. In plasminogen activation assays the inhibitory influence of the compounds did not parallel antiurokinase potency as expressed by the Ki values. This paradoxical behavior is still unexplained, but additional interaction of the compounds with plasminogen has to be considered.