Pharmacology of CS-747 (Prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity

被引:210
作者
Niitsu, Y
Jakubowski, JA
Sugidachi, A
Asai, F
机构
[1] Sankyo Co Ltd, Pharmacol & Mol Biol Res Labs, Tokyo 1408710, Japan
[2] Sankyo Co Ltd, Pharmacol & Mol Biol Res Labs, Tokyo, Japan
[3] Eli Lilly & Co, Biotechnol Discovery Res, Indianapolis, IN 46285 USA
关键词
CS-747; prasugrel; LY640315; R-138727; R-99224; platelet aggregation; antiplatelet; antithrombotic; P2Y(12) receptor antagonist; ADP;
D O I
10.1055/s-2005-869524
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 1 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.
引用
收藏
页码:184 / 194
页数:11
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