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 P2Y12 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.
KEYWORDS
CS-747 - prasugrel - LY640315 - R-138727 - R-99224 - platelet aggregation - antiplatelet - antithrombotic - P2Y12 receptor antagonist - ADP
REFERENCES
-
1
Gachet C, Hechler B, Leon C et al..
Activation of ADP receptors and platelet function.
Thromb Haemost.
1997;
78
271-275
-
2
George J N.
Platelets.
Lancet.
2000;
355
1531-1539
-
3
Jin J, Daniel J L, Kunapuli S P.
Molecular basis for ADP-induced platelet activation. II. The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets.
J Biol Chem.
1998;
273
2030-2034
-
4
Hollopeter G, Jantzen H M, Vincent D et al..
Identification of the platelet ADP receptor targeted by antithrombotic drugs.
Nature.
2001;
409
202-207
-
5
Dorsam R T, Kunapuli S P.
Central role of the P2Y12 receptor in platelet activation.
J Clin Invest.
2004;
113
340-345
-
6
McTavish D, Faulds D, Goa K L.
Ticlopidine. An updated review of its pharmacology and therapeutic use in platelet-dependent disorders.
Drugs.
1990;
40
238-259
-
7
Jarvis B, Simpson K.
Clopidogrel. A review of its use in the prevention of atherothrombosis.
Drugs.
2000;
60
347-377
-
8
A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) .
CAPRIE Steering Committee.
Lancet.
1996;
348
1329-1339
-
9
Saltiel E, Ward A.
Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states.
Drugs.
1987;
34
222-262
-
10
Gent M, Blakely J A, Easton J D et al..
The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke.
Lancet.
1989;
1
1215-1220
-
11
Page Y, Tardy B, Zeni F et al..
Thrombotic thrombocytopenic purpura related to ticlopidine.
Lancet.
1991;
337
774-776
-
12
Steinhubl S R, Tan W A, Foody J M et al..
Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting.
JAMA.
1999;
281
806-810
-
13
Bennett C L, Connors J M, Carwile J M et al..
Thrombotic thrombocytopenic purpura associated with clopidogrel.
N Engl J Med.
2000;
342
1773-1777
-
14
Zakarija A, Bandarenko N, Pandey D K et al..
Clopidogrel-associated TTP: an update of pharmacovigilance efforts conducted by independent researchers, pharmaceutical suppliers, and the Food and Drug Administration.
Stroke.
2004;
35
533-537
-
15
Jaremo P, Lindahl T L, Gransson S B et al..
Individual variations of platelet inhibition after loading doses of clopidogrel.
J Intern Med.
2002;
252
233-238
-
16
Muller I, Besta F, Schulz C et al..
Prevalence of clopidogrel nonresponders among patients with stable angina pectoris scheduled for elective coronary stent placement.
Thromb Haemost.
2003;
89
783-787
-
17
Lau W C, Waskell L A, Watkins P B et al..
Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction.
Circulation.
2003;
107
32-37
-
18
Lau W C, Gurbel P A, Watkins P B et al..
Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance.
Circulation.
2004;
109
166-171
-
19
Clarke T A, Waskell L A.
The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin.
Drug Metab Dispos.
2003;
31
53-59
-
20
Mitsios J V, Papathanasiou A I, Rodis F I et al..
Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes.
Circulation.
2004;
109
1335-1338
-
21
Sugidachi A, Asai F, Ogawa T, Inoue T, Koike H.
The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties.
Br J Pharmacol.
2000;
129
1439-1446
-
22
Sugidachi A, Asai F, Yoneda K et al..
Antiplatelet action of R-99224, an active metabolite of a novel thienopyridine-type G(i)-linked P2T antagonist, CS-747.
Br J Pharmacol.
2001;
132
47-54
-
23
Hirota T, Sugii H, Asai F et al..
Efficacy of CS-747, a new potent antiplatelet agent.
Clin Pharmacol Ther.
1999;
65
148
-
24
Quinn M J, Fitzgerald D J.
Ticlopidine and clopidogrel.
Circulation.
1999;
100
1667-1672
-
25
Di Minno G, Cerbone A M, Mattioli P L et al..
Functionally thrombasthenic state in normal platelets following the administration of ticlopidine.
J Clin Invest.
1985;
75
328-338
-
26
Coukell A J, Markham A.
Clopidogrel.
Drugs.
1997;
54
745-750
-
27
Cattaneo M, Winocour P D, Somers D A et al..
Effect of ticlopidine on platelet aggregation, adherence to damaged vessels, thrombus formation and platelet survival.
Thromb Res.
1985;
37
29-43
-
28
Jackson C W, Steward S A, Ashmun R A, McDonald T P.
Megakaryocytopoiesis and platelet production are stimulated during late pregnancy and early postpartum in the rat.
Blood.
1992;
79
1672-1678
-
29
Savi P, Pereillo J M, Uzabiaga M F et al..
Identification and biological activity of the active metabolite of clopidogrel.
Thromb Haemost.
2000;
84
891-896
-
30
Ding Z, Kim S, Dorsam R T, Jin J, Kunapuli S P.
Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270.
Blood.
2003;
101
3908-3914
-
31
Jackson S P, Schoenwaelder S M.
Antiplatelet therapy: In search of the ‘magic bullet.’
Nat Rev Drug Discov.
2003;
2
775-789
-
32
Umetsu T, Sanai K.
Effect of 1-methyl-2-mercapto-5-(3-pyridyl)-imidazole (KC-6141), an anti-aggregating compound, on experimental thrombosis in rats.
Thromb Haemost.
1978;
39
74-83
-
33
Sugidachi A, Asai F, Koike H.
In vivo pharmacology of aprosulate, a new synthetic polyanion with anticoagulant activity.
Thromb Res.
1993;
69
71-80
-
34
Asai F, Niitsu Y, Ogawa T et al..
Effects of CS-747, a novel P2Y12 receptor antagonist, on cerebral and peripheral arterial occlusive diseases in rats.
J Thromb Haemost.
2003(suppl);
2033 (abst)
-
35
Dejana E, Callioni A, Quintana A, De Gaetano G.
Bleeding time in laboratory animals. II-A comparison of different assay conditions in rats.
Thromb Res.
1979;
15
191-197
-
36
Peters R J, Mehta S R, Fox K A et al..
Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the clopidogrel in unstable angina to prevent recurrent events (CURE) study.
Circulation.
2003;
108
1682-1687
-
37
Sugidachi A, Ogawa T, Isobe T et al..
Antiplatelet and antithrombotic effects of CS-747, a novel P2Y12 receptor antagonist, in combination with aspirin.
J Thromb Haemost.
2003(suppl);
2032(abst)
-
38
Jakubowski J, Ogawa T, Sugidachi A et al..
Stereoselective inhibition of human platelet aggregation by R-138727, the active metabolite of CS-747, a novel P2Y12 receptor antagonist.
J Thromb Haemost.
2003(suppl);
2056(abst)
-
39
Gachet C.
ADP receptors of platelets and their inhibition.
Thromb Haemost.
2001;
86
222-232
-
40
Kunapuli S P.
Multiple P2 receptor subtypes on platelets: a new interpretation of their function.
Trends Pharmacol Sci.
1998;
19
391-394
-
41
Kunapuli S P.
Functional characterization of platelet ADP receptors.
Platelets.
1998;
9
343-351
-
42
Kunapuli S P, Daniel J L.
P2 receptor subtypes in the cardiovascular system.
Biochem J.
1998;
336
513-523
-
43
Daniel J L, Dangelmaier C, Jin J et al..
Molecular basis for ADP-induced platelet activation. I. Evidence for three distinct ADP receptors on human platelets.
J Biol Chem.
1998;
273
2024-2029
-
44
Boyer J L, Romero-Avila T, Schachter J B, Harden T K.
Identification of competitive antagonists of the P2Y1 receptor.
Mol Pharmacol.
1996;
50
1323-1329
-
45
Vorchheimer D A, Badimon J J, Fuster V.
Platelet glycoprotein IIb/IIIa receptor antagonists in cardiovascular disease.
JAMA.
1999;
281
1407-1414
-
46
Thebault J J, Kieffer G, Lowe G D, Nimmo W S, Cariou R.
Repeated-dose pharmacodynamics of clopidogrel in healthy subjects.
Semin Thromb Hemost.
1999;
25(Suppl 2)
9-14
Fumitoshi AsaiPh.D.
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd.
1-2-58 Hiromachi, Shinagawa-ku
Tokyo 140-8710, Japan
eMail: toasai@sankyo.co.jp