Sugidachi, A. et al. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br. J. Pharmacol. 129, 1439-1446

Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
British Journal of Pharmacology (Impact Factor: 4.84). 04/2000; 129(7):1439-46. DOI: 10.1038/sj.bjp.0703237
Source: PubMed


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.
Orally administered CS-747 (0.3–10 mg kg−1) partially but significantly decreased [3H]-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 E1, suggesting that metabolites of CS-747 interfere with Gi-linked P2T receptor.
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 (ED50 at 4 h=1.2 mg kg−1).
R-99224 (IC50=45 μM) inhibited in vitro PRP aggregation in a concentration-related manner.
CS-747 prevented thrombus formation in a dose-related manner with an ED50 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).
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.
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.
British Journal of Pharmacology (2000) 129, 1439–1446; doi:10.1038/sj.bjp.0703237

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Available from: Atsuhiro Sugidachi, Aug 15, 2014
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    • "Group III received Transamin 250mg/kg as standard while Group IV served as control and received normal saline. The bleeding time of each animal was recorded according to the reported method (Kung et al., 1998; Sugidachi et al., 2000). "
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    • "The antiaggregatory effect after a single oral dose of prasugrel was 10-fold higher compared with clopidogrel. The antithrombotic property was shown through reduced thrombus-formation in a dose-related manner with an ED50 of 0.68 mg·kg -1 for prasugrel (Sugidachi et al., 2000). The in vitro antiplatelet effect of prasugrel/clopidogrel active metabolites is almost identical, but when aggregation inhibition following a single oral dose was tested ex vivo, prasugrel was 13 times more effective than clopidogrel 4 h after intake (clopidogrel ED50: 16 mg·kg -1 , prasugrel ED50: 1.2 mg·kg -1 ) (Sugidachi et al., 2007) in rats. "
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