In our studies, designed to synthesize an active center-directed
plasmin (PL) inhibitor,
N-(4-aminomethylbenzoyl)-4-(3-picolyloxy)-L-phenylalanine n-hexylamide dihydrochloride (PASI-535) was found. We characterized
PASI-535 and analyzed the actions of PL, comparing with those of
PASI-535 and
tranexamic acid (
t-AMCHA). (1)
PASI-535 strongly inhibited not only fibrinolysis (IC50: 2.9 x 10(-6) M) but also amidolysis (Ki value: 2.9 x 10(-6) M) and fibrinogenolysis (IC50: 4.5 x 10(-6) M) induced by PL. While
t-AMCHA which strongly inhibited fibrinolysis (IC50: 6.0 x 10(-5) M), rarely inhibited amidolysis (Ki value: 4.0 x 10(-2) M) and fibrinogenolysis (IC50: 1.0 x 10(-2) M). (2) PL is able to liberate
kinins by degrading
kininogen. This
kinin-generation by PL was inhibited by 2 x 10(-5) M
PASI-535. However, it was little inhibited even by 1 x 10(-3) M
t-AMCHA. (3) The inhibitory effect of
PASI-535 and
t-AMCHA on
tumor growth was studied. In sarcoma-180 bearing mice,
ascites retention and the increase of
tumor cells were markedly suppressed by
subcutaneous injection of
PASI-535, either 30 mg/kg/day or 50 mg/kg/day, for 5 days, and the inhibitory effect was dose-dependent. Although
t-AMCHA also reduced both
ascites retention and the increase of
tumor cells, it needed approximately 40 times (2 g/kg/day) the amount of
PASI-535 to exert these effects.
PASI-535 may be a useful tool in analyzing the multiplicity of PL actions. Moreover,
PASI-535 can be used as an
antifibrinolytic drug which has a mechanism of function different from that of
t-AMCHA.