G-Protein-Coupled Receptors Signaling Pathways in New Antiplatelet Drug Development

被引:60
作者
Gurbel, Paul A. [1 ]
Kuliopulos, Athan [2 ]
Tantry, Udaya S. [1 ]
机构
[1] Sinai Hosp Baltimore, Sinai Ctr Thrombosis Res, Baltimore, MD 21215 USA
[2] Tufts Med Ctr, Ctr Hemostasis & Thrombosis Res, Boston, MA USA
关键词
blood platelet; coronary disease; GTP-binding proteins; purinerginc 2Y12 receptor agoists; receptors; thrombin; HUMAN PLATELET-AGGREGATION; THROMBIN-RECEPTOR; P2Y(12) RECEPTOR; ACTIVATED RECEPTORS; PHOSPHOINOSITIDE; 3-KINASE; ARTERIAL THROMBOSIS; IN-VITRO; TICAGRELOR; INHIBITION; ADENOSINE;
D O I
10.1161/ATVBAHA.114.303412
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Platelet G-protein-coupled receptors influence platelet function by mediating the response to various agonists, including ADP, thromboxane A(2), and thrombin. Blockade of the ADP receptor, P2Y(12), in combination with cyclooxygenase-1 inhibition by aspirin has been among the most widely used pharmacological strategies to reduce cardiovascular event occurrence in high-risk patients. The latter dual pathway blockade strategy is one of the greatest advances in the field of cardiovascular medicine. In addition to P2Y(12), the platelet thrombin receptor, protease activated receptor-1, has also been recently targeted for inhibition. Blockade of protease activated receptor-1 has been associated with reduced thrombotic event occurrence when added to a strategy using P2Y(12) and cyclooxygenase-1 inhibition. At this time, the relative contributions of these G-protein-coupled receptor signaling pathways to in vivo thrombosis remain incompletely defined. The observation of treatment failure in approximate to 10% of high-risk patients treated with aspirin and potent P2Y(12) inhibitors provides the rationale for targeting novel pathways mediating platelet function. Targeting intracellular signaling downstream from G-protein-coupled receptor receptors with phosphotidylionisitol 3-kinase and Gq inhibitors are among the novel strategies under investigation to prevent arterial ischemic event occurrence. Greater understanding of the mechanisms of G-protein-coupled receptor-mediated signaling may allow the tailoring of antiplatelet therapy.
引用
收藏
页码:500 / 512
页数:13
相关论文
共 85 条
[1]   Differential Effect of Ticagrelor Versus Prasugrel on Coronary Blood Flow Velocity in Patients With Non-ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: An Exploratory Study [J].
Alexopoulos, Dimitrios ;
Moulias, Athanasios ;
Koutsogiannis, Nikolaos ;
Xanthopoulou, Ioanna ;
Kakkavas, Apostolos ;
Mavronasiou, Eleni ;
Davlouros, Periklis ;
Hahalis, George .
CIRCULATION-CARDIOVASCULAR INTERVENTIONS, 2013, 6 (03) :277-283
[2]   Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity [J].
Andersen, H ;
Greenberg, DL ;
Fujikawa, K ;
Xu, WF ;
Chung, DW ;
Davie, EW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (20) :11189-11193
[3]   Pharmacodynamic Evaluation of Switching From Ticagrelor to Prasugrel in Patients With Stable Coronary Artery Disease Results of the SWAP-2 Study (Switching Anti Platelet-2) [J].
Angiolillo, Dominick J. ;
Curzen, Nicholas ;
Gurbel, Paul ;
Vaitkus, Paul ;
Lipkin, Fred ;
Li, Wei ;
Jakubowski, Joseph A. ;
Zettler, Marjorie ;
Effron, Mark B. ;
Trenk, Dietmar .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2014, 63 (15) :1500-1509
[4]   Bridging Antiplatelet Therapy With Cangrelor in Patients Undergoing Cardiac Surgery A Randomized Controlled Trial [J].
Angiolillo, Dominick J. ;
Firstenberg, Michael S. ;
Price, Matthew J. ;
Tummala, Pradyumna E. ;
Hutyra, Martin ;
Welsby, Ian J. ;
Voeltz, Michele D. ;
Chandna, Harish ;
Ramaiah, Chandrashekhar ;
Brtko, Miroslav ;
Cannon, Louis ;
Dyke, Cornelius ;
Liu, Tiepu ;
Montalescot, Gilles ;
Manoukian, Steven V. ;
Prats, Jayne ;
Topol, Eric J. .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2012, 307 (03) :265-274
[5]   Increased Platelet Inhibition After Switching From Maintenance Clopidogrel to Prasugrel in Patients With Acute Coronary Syndromes Results of the SWAP (SWitching Anti Platelet) Study [J].
Angiolillo, Dominick J. ;
Saucedo, Jorge F. ;
DeRaad, Roger ;
Frelinger, Andrew L. ;
Gurbel, Paul A. ;
Costigan, Timothy M. ;
Jakubowski, Joseph A. ;
Ojeh, Clement K. ;
Effron, Mark B. .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2010, 56 (13) :1017-1023
[6]   Characterization of the Adenosine Pharmacology of Ticagrelor Reveals Therapeutically Relevant Inhibition of Equilibrative Nucleoside Transporter 1 [J].
Armstrong, Duncan ;
Summers, Claire ;
Ewart, Lorna ;
Nylander, Sven ;
Sidaway, James E. ;
van Giezen, J. J. J. .
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS, 2014, 19 (02) :209-219
[7]   Matrix metalloproteases and PAR1 activation [J].
Austin, Karyn M. ;
Covic, Lidija ;
Kuliopulos, Athan .
BLOOD, 2013, 121 (03) :431-439
[8]   Lead Optimization of Ethyl 6-Aminonicotinate Acyl Sulfonamides as Antagonists of the P2Y12 Receptor. Separation of the Antithrombotic Effect and Bleeding for Candidate Drug AZD1283 [J].
Bach, Peter ;
Antonsson, Thomas ;
Bylund, Ruth ;
Bjorkman, Jan-Arne ;
Osterlund, Krister ;
Giordanetto, Fabrizio ;
van Giezen, J. J. J. ;
Andersen, Soren M. ;
Zachrisson, Helen ;
Zetterberg, Fredrik .
JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (17) :7015-7024
[9]   Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events [J].
Bhatt, Deepak L. ;
Stone, Gregg W. ;
Mahaffey, Kenneth W. ;
Gibson, C. Michael ;
Steg, P. Gabriel ;
Hamm, Christian W. ;
Price, Matthew J. ;
Leonardi, Sergio ;
Gallup, Dianne ;
Bramucci, Ezio ;
Radke, Peter W. ;
Widimsky, Petr ;
Tousek, Frantisek ;
Tauth, Jeffrey ;
Spriggs, Douglas ;
McLaurin, Brent T. ;
Angiolillo, Dominick J. ;
Genereux, Philippe ;
Liu, Tiepu ;
Prats, Jayne ;
Todd, Meredith ;
Skerjanec, Simona ;
White, Harvey D. ;
Harrington, Robert A. .
NEW ENGLAND JOURNAL OF MEDICINE, 2013, 368 (14) :1303-1313
[10]   Antagonism of P2Y12 reduces physiological thromboxane levels [J].
Bhavaraju, Kamala ;
Georgakis, Alexander ;
Jin, Jianguo ;
Gartner, Theodore Kent ;
Tomiyama, Yoshiaki ;
Nurden, Alan ;
Nurden, Paquita ;
Kunapuli, Satya P. .
PLATELETS, 2010, 21 (08) :604-609