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Atherothrombotic disease is the leading cause of death worldwide. Currently, dual antiplatelet therapy with aspirin and ADP receptor antagonists has shown improved short- and long-term clinical outcomes but is associated with increased bleeding risk, and the rates of recurrent ischemic events still remain high. Selective inhibition of the principal protease-activated receptor (PAR)-1 for thrombin, the most potent platelet activator, represents a promising novel strategy to reduce ischemic events without increasing the risk of bleeding. Two PAR-1 antagonists are currently being tested in clinical trials: SCH 530348 and E5555. Both have demonstrated an antiplatelet effect without increasing bleeding time in preclinical trials. Results of Phase II trials showed that SCH 530348, in addition to standard antiplatelet therapy, was well tolerated and not associated with increased bleeding risk. The safety and tolerability of E5555 is being evaluated in patients with coronary artery disease and non-ST-segment elevation acute coronary syndrome in four Phase II clinical trials. Two large-scale Phase III trials assessing the efficacy of SCH 530348 in addition to the standard of care are currently ongoing. This article provides an overview of the current status of knowledge on platelet thrombin receptor antagonists, focusing on pharmacologic properties and clinical development.
Division of Cardiology, Department of Medicine, University of Florida College of Medicine-Jacksonville, Shands Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA.
This article was published in the following journal.
Name: Expert review of cardiovascular therapy
A randomized trial assessing the impact of three different glycoprotein IIb/IIIa antagonists on glycoprotein IIb/IIIa platelet receptor inhibition and clinical endpoints in patients with acute coronary syndromes.
To compare three glycoprotein IIb/IIIa receptor antagonists (GPIs) in terms of platelet inhibition and major adverse cardiac events (MACEs), and assess the rate of bleeding and MACEs between GPIs and ...
Anti-platelet agents such as aspirin, clopidogrel and antagonists of integrin αIIbβ3 allowed to efficiently reduce morbidity and mortality associated with arterial thrombosis. A major limit of these...
Platelet activation plays a crucial role in hemostasis and thrombosis. Thrombin, the most potent stimulus of platelet activation, mediates platelet activation via the protease activated receptors (PAR...
Thrombin-induced platelet activation is important for arterial thrombosis. Thrombin activates human platelets predominantly via protease-activated receptors 1 (PAR1) and 4 (PAR4). PAR1 has higher affi...
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A family of proteinase-activated receptors that are specific for THROMBIN. They are found primarily on PLATELETS and on ENDOTHELIAL CELLS. Activation of thrombin receptors occurs through the proteolytic action of THROMBIN, which cleaves the N-terminal peptide from the receptor to reveal a new N-terminal peptide that is a cryptic ligand for the receptor. The receptors signal through HETEROTRIMERIC GTP-BINDING PROTEINS. Small synthetic peptides that contain the unmasked N-terminal peptide sequence can also activate the receptor in the absence of proteolytic activity.
Specific receptors on cell membranes that react with PLATELET-DERIVED GROWTH FACTOR, its analogs, or antagonists. The alpha PDGF receptor (RECEPTOR, PLATELET-DERIVED GROWTH FACTOR ALPHA) and the beta PDGF receptor (RECEPTOR, PLATELET-DERIVED GROWTH FACTOR BETA) are the two principle types of PDGF receptors. Activation of the protein-tyrosine kinase activity of the receptors occurs by ligand-induced dimerization or heterodimerization of PDGF receptor types.
The attachment of PLATELETS to one another. This clumping together can be induced by a number of agents (e.g., THROMBIN; COLLAGEN) and is part of the mechanism leading to the formation of a THROMBUS.
Platelet membrane glycoprotein complex essential for normal platelet adhesion and clot formation at sites of vascular injury. It is composed of three polypeptides, GPIb alpha, GPIb beta, and GPIX. Glycoprotein Ib functions as a receptor for von Willebrand factor and for thrombin. Congenital deficiency of the GPIb-IX complex results in Bernard-Soulier syndrome. The platelet glycoprotein GPV associates with GPIb-IX and is also absent in Bernard-Soulier syndrome.
A serotonin receptor subtype found primarily in the CENTRAL NERVOUS SYSTEM and the CHOROID PLEXUS. This receptor subtype is believed to mediate the anorectic action of SEROTONIN, while selective antagonists of the 5-HT2C receptor appear to induce ANXIETY. Several isoforms of this receptor subtype exist, due to adenine deaminase editing of the receptor mRNA.
In a clinical trial or interventional study, participants receive specific interventions according to the research plan or protocol created by the investigators. These interventions may be medical products, such as drugs or devices; procedures; or change...
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