Summary
A series of peptide aldehydes synthetized in our institute during the last 15 years
were screened to detect their inhibitory effect on blood coagulation. Simple conventional
clotting assays, platelet function tests and fibrinolytic methods were used to evaluate
the inhibitory potency of the compounds in complex clotting systems as well as their
supposed antifibrinolytic effect in vitro. Special attention was paid to the possible
interactions with blood cells and plasma proteins, and to the functional stability
of the inhibitors in several tissue homogenates. D-Phe-Pro-Arg-H (GYKI-14166, RGH-2958),
Boc-D-Phe-Pro-Arg-H (GYKI-14451) and D-MePhe-Pro-Arg-H (GYKI-14766) were found to
be the most potent inhibitors. The peptide aldehydes via formation of reversible complexes
with thrombin impede the enzyme to react with the coagulation factors, platelet membrane
and vessel wall. The compounds inhibit platelet aggregation induced by thrombin specifically
without changing the sensitivity of platelets to other inducers. D-Phe-Pro-Arg-H and
D-MePhe-Pro-Arg-H showed no antifibrinolytic effect. D-MePhe-Pro-Arg-H and Boc-D-Phe-Pro-Arg-H
proved to be stable in dry state for years and in solution at room temperature for
several days. The anticoagulant activity of the compounds was declared in NIH antithrombin
units.
