Antithrombotic drug market

Collins, B K; Hollidge, Christine

doi:10.1038/nrd966

Cited by 39 publications

(19 citation statements)

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“…AR-C69931MX is a P2Y 12 antagonist, which has entered into phase II clinical trial and was recently halted in development as an antiplatelet drug by AstraZeneca because of poor oral availability and the lack of commercial potential as an injectable antiplatelet drug (Ingall et al, 1999;Huang et al, 2000;Jacobsson et al, 2002;Collins and Hollidge, 2003). We found that AR-C69931MX has no effects on the constitutive activity of the chimeric P2Y 12 up to 300 nM (Fig.…”

Section: Construction and Stable Expression Of Wild-type And Chimericmentioning

confidence: 88%

Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y₁₂ Receptor

2005

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Human platelets express two P2Y receptors: G q -coupled P2Y 1 , and G i -coupled P2Y 12 . Both P2Y 1 and P2Y 12 are ADP receptors on human platelets and are essential for ADP-induced platelet aggregation that plays pivotal roles in thrombosis and hemostasis. Numerous constitutively active G protein-coupled receptors have been described in natural or recombinant systems, but in the P2Y receptors, to date, no constitutive activity has been reported. In our effort to identify G protein coupling domains of the human platelet ADP receptor, we constructed a chimeric hemagglutinin-tagged human P2Y 12 receptor with its C terminus replaced by the corresponding part of human P2Y 1 receptor and stably expressed it in Chinese hamster ovary-K1 cells. It is interesting that the chimeric P2Y 12 mutant exhibited a high level of constitutive activity, as evidenced by decreased cAMP levels in the absence of agonists. The constitutive activation of the chimeric P2Y 12 mutant was dramatically inhibited [(3,3,3-trifluoropropyl)thio]-, monoanhydride with (dichloromethylene)bis[phosphonic acid] (AR-C69931MX) as a neutral antagonist. In conclusion, this is the first report of a cell line stably expressing a constitutively active mutant of human platelet P2Y 12 receptor and the identification of potent inverse agonist.

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Section: Construction and Stable Expression Of Wild-type And Chimericmentioning

confidence: 88%

Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y₁₂ Receptor

2005

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“…However, their unnecessary activation is often linked to life-threatening thrombotic diseases including venous and arterial thrombosis, embolism and stroke (Coller, 2013). Numerous drugs modulating platelet activation have been developed and are hugely successful in the market for the prevention of thrombotic diseases and thrombotic complications in diverse cardiovascular diseases, exemplified by aspirin, Plavix (Bristol-Myers Squibb, NY, USA; clopidogrel), Efient (Lilly, Indianapolis, IN, USA; prasugrel) and Pletal (Otsuka, Tokyo, Japan; cilostazol) (Collins and Hollidge, 2003; Rao et al ., 2006). In contrast to aggregation or adhesion, functions that are well-illustrated in the thrombus formation, role of the morphological changes of platelet, i.e., platelet shape change, is relatively less established.…”

Section: Introductionmentioning

confidence: 99%

Platelet Shape Changes and Cytoskeleton Dynamics as Novel Therapeutic Targets for Anti-Thrombotic Drugs

Shin

Park

Noh

et al. 2017

Biomolecules & Therapeutics

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Platelets play an essential role in hemostasis through aggregation and adhesion to vascular injury sites but their unnecessary activation can often lead to thrombotic diseases. Upon exposure to physical or biochemical stimuli, remarkable platelet shape changes precede aggregation or adhesion. Platelets shape changes facilitate the formation and adhesion of platelet aggregates, but are readily reversible in contrast to the irrevocable characteristics of aggregation and adhesion. In this dynamic phenomenon, complex molecular signaling pathways and a host of diverse cytoskeleton proteins are involved. Platelet shape change is easily primed by diverse pro-thrombotic xenobiotics and stimuli, and its inhibition can modulate thrombosis, which can ultimately contribute to the development or prevention of thrombotic diseases. In this review, we discussed the current knowledge on the mechanisms of platelet shape change and also pathological implications and therapeutic opportunities for regulating the related cytoskeleton dynamics.

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“…Given the central role played by platelets in the pathogenesis of atherothrombosis, a variety of antiplatelet agents have been developed to prevent thrombotic ischemic events [36]. Although antiplatelet drugs have being used widely in the management of acute episodes and secondary prevention, its effectiveness in primary prevention is still a matter of debate, and CVDs still represent the leading causes of morbidity and mortality, worldwide [37].…”

Section: Discussionmentioning

confidence: 99%

Protective Mechanisms ofS. lycopersicumAqueous Fraction (Nucleosides and Flavonoids) on Platelet Activation and Thrombus Formation:In Vitro,Ex VivoandIn VivoStudies

Fuentes

Pereira

Alarcón

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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The purpose of this research was to investigate mechanisms of antiplatelet action of bioactive principle from S. lycopersicum. Aqueous fraction had a high content of nucleosides (adenosine, guanosine, and adenosine 5′-monophosphate) by HPLC analysis. Also aqueous fraction presented flavonoids content. Aqueous fraction inhibited platelet activation by 15 ± 6% (P < 0.05). Fully spread of human platelets on collagen in the presence of aqueous fraction was inhibited from 15 ± 1 to 9 ± 1 μm2 (P < 0.001). After incubation of whole blood with aqueous fraction, the platelet coverage was inhibited by 55 ± 12% (P < 0.001). Platelet ATP secretion and aggregation were significantly inhibited by the aqueous fraction. At the same concentrations that aqueous fraction inhibits platelet aggregation, levels of sCD40L significantly decreased and the intraplatelet cAMP levels increased. In addition, SQ22536, an adenylate cyclase inhibitor, attenuated the effect of aqueous fraction toward ADP-induced platelet aggregation and intraplatelet level of cAMP. Platelet aggregation ex vivo (human study) and thrombosis formation in vivo (murine model) were inhibited by aqueous fraction. Finally, aqueous fraction may be used as a functional ingredient adding antiplatelet activities (nucleosides and flavonoids) to processed foods.

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Antithrombotic drug market

Cited by 39 publications

References 1 publication

Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y₁₂ Receptor

Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y₁₂ Receptor

Platelet Shape Changes and Cytoskeleton Dynamics as Novel Therapeutic Targets for Anti-Thrombotic Drugs

Protective Mechanisms ofS. lycopersicumAqueous Fraction (Nucleosides and Flavonoids) on Platelet Activation and Thrombus Formation:In Vitro,Ex VivoandIn VivoStudies

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Antithrombotic drug market

Cited by 39 publications

References 1 publication

Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y12 Receptor

Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y12 Receptor

Platelet Shape Changes and Cytoskeleton Dynamics as Novel Therapeutic Targets for Anti-Thrombotic Drugs

Protective Mechanisms ofS. lycopersicumAqueous Fraction (Nucleosides and Flavonoids) on Platelet Activation and Thrombus Formation:In Vitro,Ex VivoandIn VivoStudies

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Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y₁₂ Receptor

Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y₁₂ Receptor