title: The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties.
abstract: 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.
authors.affiliation: Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Sugidachi
authors.forename: F
authors.initials: F
authors.lastname: Asai
authors.forename: T
authors.initials: T
authors.lastname: Ogawa
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: H
authors.initials: H
authors.lastname: Koike
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001667:Binding, Competitive / Q000187:drug effects; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000077144:Clopidogrel; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D000068799:Prasugrel Hydrochloride; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D013873:Thionucleotides / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000517:prevention & control; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D014316:Tritium
chemical_list: D005343:Fibrinolytic Agents; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D013873:Thionucleotides; D013876:Thiophenes; D014316:Tritium; C002480:methylthio-ADP; D000244:Adenosine Diphosphate; D003094:Collagen; D000077144:Clopidogrel; D000242:Cyclic AMP; D013917:Thrombin; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine