Mode of action of P2Y12 antagonists as inhibitors of platelet function

Thrombosis and Haemostasis

Volumn 105, Issue 1, 2011, Pages 96-106

  Iyú, David ^a   Glenn, Jackie R ^a   White, Ann E ^a   Fox, Sue C ^a   Van Giezen, Hans ^b   Nylander, Sven ^b   Heptinstall, Stan ^a  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^b ASTRAZENECA R AND D   (Sweden)

Author keywords

ADP; Gs coupled receptors; P2Y12 antagonists; Platelet aggregation; VASP phosphorylation

Indexed keywords

15 HYDROXY 11ALPHA,9ALPHA EPOXYMETHANOPROSTA 5,13 DIENOIC ACID; 5 AMINO 2 (2 FURYL) 7 (2 PHENYLETHYL)PYRAZOLO[4,3 E][1,2,4]TRIAZOLO[1,5 C]PYRIMIDINE; ADENOSINE DEAMINASE; ADENOSINE DIPHOSPHATE; APYRASE; CANGRELOR; CAY 10441; CYCLIC AMP; G PROTEIN COUPLED RECEPTOR; ILOPROST; ONO AE1 329; PRASUGREL; PURINERGIC P2Y12 RECEPTOR; RECEPTOR BLOCKING AGENT; SULPROSTONE; THROMBIN RECEPTOR ACTIVATING PEPTIDE; TICAGRELOR; UNCLASSIFIED DRUG; VASODILATOR STIMULATED PHOSPHOPROTEIN;

ANTICOAGULATION; ARTICLE; CONTROLLED STUDY; DRUG MECHANISM; DRUG RECEPTOR BINDING; FLOW CYTOMETRY; HUMAN; HUMAN CELL; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; THROMBOCYTE AGGREGATION; THROMBOCYTE AGGREGATION INHIBITION; THROMBOCYTE FUNCTION;

ADENOSINE; ADENOSINE MONOPHOSPHATE; BLOOD PLATELETS; CELL ADHESION MOLECULES; CELLS, CULTURED; HUMANS; MICROFILAMENT PROTEINS; PHOSPHOPROTEINS; PHOSPHORYLATION; PIPERAZINES; PLATELET AGGREGATION INHIBITORS; PURINERGIC P2Y RECEPTOR ANTAGONISTS; RECEPTORS, G-PROTEIN-COUPLED; THIOPHENES;

EID: 78651104451     PISSN: 03406245     EISSN: None     Source Type: Journal    
DOI: 10.1160/TH10-07-0482     Document Type: Article

References (42)

1. Heemskerk JWM, et al. Platelet activation and blood coagulation. Thromb Haemost 2002; 88: 186-193.
2. Munix ICA, et al. Platelet response heterogeneity in thrombus formation. Thromb Haemost 2009; 102: 1149-1156.
3. 2T receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol 2000; 110: 925-934.
4. Storey RF, et al. Inhibition of ADP-induced P-selectin expression and platelet-leukocyte conjugate formation by clopidogrel and the P2Y12 receptor antagonist AR-C69931MX but not aspirin. Thromb Haemost 2002; 88: 488-494.
5. 12 receptor in platelet activation. J Clin Invest 2004; 113: 340-344.
6. Gachet C. P2 receptors, platelet function and pharmacological implications. Thromb Haemost 2008; 99: 466-472.
7. 12 receptor influences the vessel wall response to arterial injury and thrombosis. Circulation 2009; 119: 116-122.
8. Judge HM, et al. Relationship between degree of P2Y12 receptor blockade and inhibition of P2Y12-mediated platelet function. Thromb Haemost 2010;103: 1210-1217.
9. 12 inhibitors. Circulation 2010; 121: 171-179.
10. Becker RC, Gurbel PA. Platelet P2Y12 receptor antagonist pharmacokinetics and pharmacodynamics: a foundation for distinguishing mechanisms of bleeding and anticipated risk for platelet-directed therapies. Thromb Haemost 2010;103: 535-544.
11. Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discovery 2010; 9: 154-169.
12. Zürn C, et al. ADP-receptor blockade: A case for personalised pharmacotherapy? Thromb Haemost 2010; 103: 496-506.
13. Savi P, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-896.
14. 12 receptor oligomers and partitions them out of lipid rafts. Proc Natl Acad Sci 2006; 103: 11069-11074.
15. 12 receptor by thiol reagents requires interaction with both extracellular cysteine residues Cyst 17 and Cyst 270. Blood 2003; 101: 3908-3914.
16. 12 receptor. J Thromb Haemost 2008; 6: 1908-1914.
17. 12 receptors independently from ADP but antagonizes ADP-induced receptor signalling and platelet aggregation. J Thromb Haemost 2009; 7: 1556-1565.
18. 2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes. Thromb Haemost 2001; 85:401-407.
19. van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost 2005; 21: 195-204.
20. 12 antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function. J Thromb Haemost 2010; 6: 1153-1159
21. Paul BZ, et al. Distribution of prostaglandins IP and EP receptor subtypes and isoforms in platelets and human umbilical artery smooth muscle cells. Br J Haematol 1998; 102: 1204-1211.
22. 2 on human platelet function. Platelets 2010; 21:329-342.
23. 2A Adenosine receptors in peripheral blood cells. Br J Pharmacol 2000; 129: 2-11.
24. 3 receptor. Thromb Haemost 2008; 100: 261-270.
25. Heptinstall S, et al. DG-041 inhibits the EP3 prostanoid receptor-a new target for inhibition of platelet function in atherothrombotic disease Platelets 2008; 19: 605-613
26. Singh J, et al. Antagonists of the EP3 receptor for prostaglandin E2 are novel antiplatelet agents that do not prolong bleeding. ACS Chem Biol 2009; 4: 115-126.
27. Dohlman HG, et al. Model system for the study of seven-transmembrane- segment receptors. Ann Rev Biochem 1991; 60: 653-688.
28. Narumiya S, et al. Prostanoid receptors: structures, properties and functions. Physiol Rev 1999; 79: 1193-1226.
29. i-independent increase in cAMP levels. J Biol Chem 2009; 284: 16108-16117.
30. Wallentin L, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
31. Sugimoto Y, Narumiya S. Prostaglandin E receptor. J Biol Chem 2007; 282: 11613-11617.
32. Foudi N, et al. Vasorelaxation induced by prostaglandin E2 in human pulmonary vein: role of the EP3 receptor subtype. Br J Pharmacol 2008; 154: 1631-1639.
33. 4 receptors to induce IL-18 production in human colonic epithelial cells. Br J Pharmacol 2009; 156: 475-485.
34. Haslam RJ, McClenaghan MD. Measurement of circulating prostacyclin. Nature 1981; 292: 364-366.
35. Horn EH, et al. A cross-sectional study of platelet cyclic AMP in healthy and hypertensive pregnant women. Clin Sci 1991; 80: 549-558.
36. 1 receptor. Mol Pharmacol 2001; 60: 432-439.
37. 12 receptor inhibitor. Thromb Haemost 2005; 94: 593-598.
38. Nolte C, et al. Comparison of vasodilatory prostaglandins with respect to cAMP-mediated phosphorylation of a target substrate in intact human platelets. Biochem Pharmacol 1991; 42: 253-262.
39. Xiange B, et al. A Gi-independent mechanism mediating Akt phosphorylation in platelets. J Thromb Haemost 2010; Epub ahead of print.
40. 12 receptor. Mol Pharmacol 2006; 69: 338-345.
41. Chee MJS, et al. The third intracellular loop stabilizes the inactive state of the neuropeptide Y1 receptor. J Biol Chem 2008; 283: 33337-33346
42. Björkman JA, et al. AZD6140 inhibits adenosine uptake into erythrocytes and enhances coronary blood flow after local ischemia or intracoronary adenosine infusion. Circulation 2007; 116 (Suppl): II-28 [Abstract 245].