title: Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity.
abstract: CS-747 (prasugrel, LY640315) is a member of the thienopyridine class of oral platelet aggregation inhibitors that includes ticlopidine and clopidogrel. A single oral administration of CS-747 produced a dose-related inhibition of platelet aggregation in rats that was approximately 10- and 100-fold more potent than that of clopidogrel and ticlopidine, respectively. The antiaggregatory effect of CS-747 was evident at 30 minutes and lasted until 72 hours after dosing, indicating fast onset and long duration of action. CS-747 showed more potent antithrombotic activity compared with clopidogrel and ticlopidine with the same rank order as the antiaggregatory potencies. Combined administration of CS-747 with aspirin to rats produced substantially greater inhibition of both platelet aggregation and thrombus formation compared with each agent alone. The antiplatelet action of CS-747 is due to irreversible and selective blockade of platelet P2Y (12) adenosine diphosphate (ADP) receptors by its active metabolite R-138727. In phase I studies, a single oral dose of CS-747 (30 and 75 mg) produced > 50% inhibition of ADP-induced platelet aggregation, with rapid onset (1 hour) and long duration (> 48 hours) of action. In healthy volunteers, once-daily administration of 10 mg CS-747 for 10 days showed significant cumulative inhibition of platelet aggregation from 2 days after the first dose until at least 2 days after the final dose. Studies conducted to date indicate that CS-747 is a highly effective antiplatelet and antithrombotic agent and is anticipated to be effective in the treatment of atherothrombotic and other ischemic vascular diseases.
authors.affiliation: Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Niitsu
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sugidachi
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Asai
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001711:Biotransformation; D017321:Clinical Trials, Phase I as Topic; D000077144:Clopidogrel; D003094:Collagen / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D015394:Molecular Structure; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000068799:Prasugrel Hydrochloride; D011355:Prodrugs / Q000493:pharmacokinetics; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000502:physiology; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000188:drug therapy; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D005343:Fibrinolytic Agents; D008565:Membrane Proteins; C548576:P2RY12 protein, human; C553058:P2ry12 protein, rat; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; C446540:thienopyridine; D000244:Adenosine Diphosphate; D003094:Collagen; D000077144:Clopidogrel; D013917:Thrombin; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine; D001241:Aspirin