1.
CS-747 is a novel
antiplatelet agent that generates an active metabolite,
R-99224, in vivo.
CS-747 itself was totally inactive in vitro. This study examined in vivo pharmacological profiles of
CS-747 after single
oral administration to rats. 2. Orally administered
CS-747 (0.3 - 10 mg kg(-1)) partially but significantly decreased [(3)H]-2-
methylthio-ADP binding to rat platelets.
CS-747 (3 mg kg(-1), p.o.) treatment neutralized
ADP-induced decreases of
cyclic AMP concentrations induced by
prostaglandin E(1), suggesting that metabolites of
CS-747 interfere with G(i)-linked P2T receptor. 3.
CS-747 (0.3 and 3 mg kg(-1), p.o.) markedly inhibited ex vivo washed platelet aggregation in response to
ADP but not to
thrombin.
CS-747 also exhibited a marked inhibition of
ADP-induced ex vivo platelet aggregation in PRP with a rapid onset (<0.5 h) and long duration (>3 days) of action (ED(50) at 4 h=1.2 mg kg(-1)). 4.
R-99224 (IC(50)=45 microM) inhibited in vitro PRP aggregation in a concentration-related manner. 5.
CS-747 prevented
thrombus formation in a dose-related manner with an ED(50) value of 0.68 mg kg(-1).
CS-747 was more potent than
clopidogrel (6.2 mg kg(-1)) and
ticlopidine (>300 mg kg(-1)). 6.
CS-747,
clopidogrel, and
ticlopidine prolonged the bleeding time. The order of potency of these agents in this activity was the same as that in antiaggregatory and antithrombotic activities. 7. These findings indicate that
CS-747 is an orally active and a potent antiplatelet and
antithrombotic agent with a rapid onset and long duration of action, and warrants clinical evaluations of the agent.