Blockade of the Thrombin Receptor Protease-Activated Receptor-1 with a Small-Molecule Antagonist Prevents Thrombus Formation and Vascular Occlusion in Nonhuman Primates

Derian, Claudia K.; Damiano, Bruce P.; Addo, Marylyn M.; Darrow, Andrew L.; D’Andrea, Michael R.; Nedelman, Mark; Zhang, Han‐Cheng; Maryanoff, Bruce E.; Andrade‐Gordon, Patricia

doi:10.1124/jpet.102.042663

Cited by 154 publications

(133 citation statements)

References 36 publications

(52 reference statements)

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“…Similar to the preliminary clinical evidence discussed above, which suggests that PAR-1 inhibition may not be associated with increased bleeding risk, the absence of an adverse impact on bleeding parameters has also been reported in preclinical studies with SCH530348 20) and other PAR-1 antagonists 15,21) . Additionally, genetic inactivation of the principal thrombin receptor on mouse platelets (PAR-4, which corresponds to PAR-1 on human platelets) does not result in spontaneous bleeding 22) .…”

Section: Discussionsupporting

confidence: 55%

Safety and Exploratory Efficacy of the Novel Thrombin Receptor (PAR-1) Antagonist SCH530348 for Non-ST-Segment Elevation Acute Coronary Syndrome

Goto

Yamaguchi

Ikeda

et al. 2010

JAT

103

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Aim: A previous phase 2 study of patients undergoing non-urgent PCI treated with SCH530348 plus aspirin and clopidogrel tended to reduce MACE without increased bleeding. This study evaluated the safety of SCH530348 in Japanese patients with NSTE ACS. Methods: Subjects (117), in whom PCI was planned, received standard-of-care (aspirin, ticlopidine, and heparin) and were randomized 4:1 to receive either SCH530348 (20 or 40 mg loading dose followed by 1 mg/d or 2.5 mg/d for 60 days) or placebo. The key safety endpoint was TIMI major and minor bleeding in the PCI cohort (n 92). The key exploratory efficacy endpoint was MACE and death within 60 days. Addition of SCH530348 to standard-of-care did not significantly increase the rate of TIMI major and minor bleeding (or non-TIMI bleeding) in the primary cohort. Results: Incidence (non-MACE) and discontinuation of AEs were similar across groups. PCI subjects treated with SCH530348 plus standard-of-care experienced a significant reduction in periprocedural MI compared with standard-of-care alone (16.9% vs 42.9%, respectively; p 0.013). There were no deaths or any other MACE. Conclusion: SCH530348 added to standard-of-care did not result in excess bleeding in Japanese subjects with NSTE ACS but significantly reduced the incidence of periprocedural MI in subjects undergoing urgent PCI. J Atheroscler Thromb, 2010; 17:156-164.

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Section: Discussionsupporting

confidence: 55%

Safety and Exploratory Efficacy of the Novel Thrombin Receptor (PAR-1) Antagonist SCH530348 for Non-ST-Segment Elevation Acute Coronary Syndrome

Goto

Yamaguchi

Ikeda

et al. 2010

JAT

103

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“…75 While PAR-3 and PAR-4 knockout mice are protected against thrombosis and demonstrate defective thrombus formation, 75,76 direct PAR-1 inhibition in primate models also abrogates arterial thrombosis. 77 In humans, PARs may also be significantly implicated in atherothrombosis by acting in other cells. 61 For instance, PAR-1 mediated activation of endothelial cells by thrombin triggers release of VWF and surface expression of P-selectin, facilitating the rolling and adhesion of platelets and leukocytes.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

“…77 In humans, PARs may also be significantly implicated in atherothrombosis by acting in other cells. 61 For instance, PAR-1 mediated activation of endothelial cells by thrombin triggers release of VWF and surface expression of P-selectin, facilitating the rolling and adhesion of platelets and leukocytes.…”

mentioning

confidence: 99%

Platelet receptors and signaling in the dynamics of thrombus formation

Rivera¹,

Lozano²,

et al. 2009

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Hemostasis and pathological thrombus formation are dynamic processes that require a co-ordinated series of events involving platelet membrane receptors, bidirectional intracellular signals, and release of platelet proteins and inflammatory substances. This review aims to summarize current knowledge in the key steps in the dynamics of thrombus formation, with special emphasis on the crucial participation of platelet receptors and signaling in this process. Initial tethering and firm adhesion of platelets to the exposed subendothelium is mediated by glycoprotein (GP) Ib/IX/V complex and collagen receptors, GP VI and α2β1 integrin, in the platelet surface, and by VWF and fibrillar collagen in the vascular site. Interactions between these elements are largely influenced by flow and trigger signaling events that reinforce adhesion and promote platelet activation. Thereafter, soluble agonists, ADP, thrombin, TxA2, produced/released at the site of vascular injury act in autocrine and paracrine mode to amplify platelet activation and to recruit circulating platelets to the developing thrombus. Specific interactions of these agonists with their G-protein coupled receptors generate inside-out signaling leading to conformational activation of integrins, in particular αIIbβ3, increasing their ligand affinity. Binding of αIIbβ3 to its ligands, mainly fibrinogen, supports processes such as clot retraction and platelet aggregation. Stabilization of thrombi is supported by the late wave of signaling events promoted by close contact between aggregated platelets. The best known contact-dependent signaling is outside-in signaling through αIIbβ3, but new ones are being clarified such as those mediated by interaction of Eph receptors with ephrins, or by Sema 4D and Gas-6 binding to their receptors. Finally, newly identified mechanisms appear to control thrombus growth, including back-shifting of activated integrins and actuation of compensatory molecules such as ESAM or PECAM-1. The expanding knowledge of thrombotic disease is expected to translate into the development of new drugs to help management and prevention of thrombosis.Key words: platelet, receptors, thrombus formation.Citation: Rivera J, Lozano ML, Navarro-Núñez L, Vicente V. Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 2009; 94:700-711. doi:10.3324/haematol.2008 This is an open-access paper. ABSTRACT Platelet receptors and signaling in the dynamics of thrombus formationJosé Rivera, María Luisa Lozano, Leyre Navarro-Núñez, and Vicente Vicente Unit of Hematology and Clinical Oncology, Centro Regional de Hemodonación, University of Murcia, Spain © F e r r a t a S t o r t i F o u n d a t i o nand metastasis, or immunological host defense. 1Internally, platelets contain a cytoskeleton, a dense tubular system, few mitochondrias, glycogen granules, dense (δ) and α storage granules and peroxisomes. The α-granules retain relevant proteins for the hemostatic function of platelets, such as von Willebrand factor (VWF), fibrinogen, P-selectin,...

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“…[95][96][97][98] Some PAR1 antagonists have been reported to prevent the development of vascular restenosis after balloon angioplasty and thrombotic occlusive lesions, in the animal models. 97,99 Further investigation and identification of the involvement of PARs in other vascular diseases would broaden the application of the PAR1 antagonists. A small molecule antagonist for PAR2 has recently been reported, 100 whereas the conventional receptor antagonists for PAR3 or PAR4 have yet to be developed.…”

Section: The Possibility Of Pars As Therapeutic Targets For Vascular mentioning

confidence: 99%

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

Hirano

2007

ATVB

136

121

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Abstract-Proteinase-activated receptors (PARs) belong to a family of G protein-coupled receptors, thus mediating the cellular effects of proteinases. In the vascular system, thrombin and other proteinases in the coagulation-fibrinolysis system are considered to be the physiologically relevant agonists, whereas PARs are among the most important mechanisms mediating the interaction between the coagulation-fibrinolysis system and the vascular wall. Under physiological conditions, PARs are mainly expressed in endothelial cells, and participate in the regulation of vascular tone, mostly by inducing endothelium-dependent relaxation. PARs in endothelial cells are also suggested to contribute to a proinflammatory phenotypic conversion and an increase in the permeability of vascular lesions. In smooth muscle cells, PARs mediate contraction, migration, proliferation, hypertrophy, and production of the extracellular matrix, thereby contributing to the development of vascular lesions and the pathophysiology of such vascular diseases as atherosclerosis. However, the expression of PARs in the smooth muscle of normal arteries is limited. The upregulation of PARs in the smooth muscle is thus considered to be a key step for PARs to participate in the pathogenesis of vascular lesions. Elucidating the molecular mechanism regulating the PARs expression is therefore important to develop new strategies for the prevention and treatment of vascular diseases. (Arterioscler Thromb Vasc Biol. 2007;27:27-36.)

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Blockade of the Thrombin Receptor Protease-Activated Receptor-1 with a Small-Molecule Antagonist Prevents Thrombus Formation and Vascular Occlusion in Nonhuman Primates

Cited by 154 publications

References 36 publications

Safety and Exploratory Efficacy of the Novel Thrombin Receptor (PAR-1) Antagonist SCH530348 for Non-ST-Segment Elevation Acute Coronary Syndrome

Safety and Exploratory Efficacy of the Novel Thrombin Receptor (PAR-1) Antagonist SCH530348 for Non-ST-Segment Elevation Acute Coronary Syndrome

Platelet receptors and signaling in the dynamics of thrombus formation

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

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