Mechanism of action and clinical development of platelet thrombin receptor antagonists.

06:00 EDT 31st July 2010 | BioPortfolio

Summary of "Mechanism of action and clinical development of platelet thrombin receptor antagonists."

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.

Journal Details

This article was published in the following journal.

Name: Expert review of cardiovascular therapy
ISSN: 1744-8344
Pages: 1191-200


PubMed Articles [42112 Associated PubMed Articles listed on BioPortfolio]

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4.

Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existen...

Current basis for discovery and development of aryl Hydrocarbon receptor antagonists for experimental and therapeutic use in atherosclerosis.

The important role played by aryl hydrocarbon receptor activation in the pathophysiology of atherosclerosis induced by cigarette smoke exposure has spurred the clinical interest in the development of ...

Heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a clinical immune-mediated syndrome; symptoms of HIT result from the development of arterial and venous thrombosis and are correlated with the severity of the...

Protease activated receptor-1 antagonist ameliorates the clinical symptoms of experimental autoimmune encephalomyelitis via inhibiting breakdown of blood brain barrier.

To evaluate the question of whether protease activated receptor-1 (PAR-1) antagonist is a potential therapeutic target in multiple sclerosis, we treated experimental autoimmune encephalomyelitis (EAE)...

New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors.

Currently approved platelet adenosine diphosphate (ADP) receptor antagonists target only the platelet P2Y12 receptor. Moreover, especially in patients with acute coronary syndromes, there is a strong ...

Clinical Trials [4805 Associated Clinical Trials listed on BioPortfolio]

The Role of the P2Y12 Receptor in Tissue Factor Induced Coagulation

Severe sepsis still carries a high mortality rate despite advantages in intensive care medicine and antimicrobial therapy. The inflammatory and procoagulant host response to infection are ...

Postoperative Pain and Angiotensin II Receptor Antagonists

An angiotensin II type 2 receptor (AT2R) antagonist has been assessed for its efficacy in neuropathic pain with promising results. A considerable number of patients undergoing surgery unde...

Vorapaxar in Patients With Prior Myocardial Infarction Treated With Prasugrel and Ticagrelor

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor represents the standard of care for the long-term secondary prevention of atherothrombotic events in patients w...

Evaluation of the Mechanism of Action of Platelet Rich Fibrin Matrix (PRFM) in Producing Skin Volume Augmentation

Autologous platelet rich fibrin matrix will release growth factors which could increase the production of dermal proteins or affect the vascularity and status of neighboring tissues. This ...

Prevention of Endoleaks Using Autologous Platelet Gel on Unruptured Abdominal Aortic Aneurysms

The main risk of aortic aneurysms is rupture that leads to a high risk of death. A preventive surgical treatment is thus needed. In order to reduce the morbidity and mortality associated w...

Medical and Biotech [MESH] Definitions

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.


Relevant Topics

Clincial Trials
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...

Cardiology is a specialty of internal medicine.  Cardiac electrophysiology : Study of the electrical properties and conduction diseases of the heart. Echocardiography : The use of ultrasound to study the mechanical function/physics of the h...

Searches Linking to this Article