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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    ABSTRACT: Prasugrel, a thienopyridine anti-platelet drug, is converted in animals and humans to the pharmacologically active metabolite (R-138727, (2Z)-{1-[(1RS)-2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanylpiperidin-3-ylidene}ethanoic acid) that has 2 chiral centers, occurring as a mixture of 4 isomers. The RS- and RR-isomers are more active than the SS- and SR-isomers (RS > RR > SR = SS). The pharmacologically active metabolite is further metabolized to an S-methylated metabolite that is the major identified inactive metabolite in humans . In rat, dog and human liver microsomes supplemented with S-adenosyl methione, the SS- and SR-isomers of the active metabolite were extensively S-methylated, while the RS- and RR-isomers were not. Addition of 2,3-dichloromethyl benzylamine (50 μM) completely inhibited the S-methylation reaction, indicating that the microsomal and cytosolic thiol methyltransferase but not the cytosolic thiopurine S-methyltransferase is involved in the methylation. The hepatic intrinsic clearance values for methylation of the RS-, RR-, SS- and SR-isomers (mL/min/kg) were 0, 0, 40.4 and 37.6, respectively, in rat liver microsomes, 0, 0, 11.6 and 2.5, respectively, in dog liver microsomes, and 0, 0, 17.3 and 17.7, respectively, in human liver microsomes, indicating that the RS- and RR-isomers are not methylated in vitro and that the methylation of SS- and SR-isomers is high with rat > human > dog. This finding in vitro agreed well with the in vivo observation in rats and dogs, where the S-methylated SS- and SR-isomers were the major metabolites in the plasma while negligible amounts of S-methylated RS- and RR-isomers were detected after intravenous administration of the pharmacologically active metabolites.
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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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