P2Y1 receptor antagonists as novel antithrombotic agents

Pfefferkorn, Jeffrey A.; Choi, Chulho; Winters, Thomas; Kennedy, Robert M.; Chi, Liguo; Perrin, Lisa A.; Lu, Gina H.; Ping, Yun-Wen; McClanahan, Tom; Schroeder, Richard L.; Leininger, Michael T.; Geyer, Andrew; Schefzick, Sabine; Atherton, James

doi:10.1016/j.bmcl.2008.04.028

Cited by 45 publications

(24 citation statements)

References 24 publications

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“…However, due to their limited bioavailability for long-term treatment, new P2Y 1 receptor antagonists with improved pharmacokinetic profile will need to be developed. Several non-nucleotide antagonists of this receptor have been described such as tetrahydro-quinolinamine inhibitors [124], aryl-urea inhibitors [125] and benzofuransubstituted urea derivatives [126] which display however lower affinity for the receptor. Whether these compounds fulfil these latter criteria and are effective in vivo remain to be investigated.…”

Section: The P2y 1 Receptor As a Target For New Antiplatelet Compoundsmentioning

confidence: 99%

P2 receptors and platelet function

Hechler

Gachet

2011

Purinergic Signalling

136

127

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Following vessel wall injury, platelets adhere to the exposed subendothelium, become activated and release mediators such as TXA 2 and nucleotides stored at very high concentration in the so-called dense granules. Released nucleotides and other soluble agents act in a positive feedback mechanism to cause further platelet activation and amplify platelet responses induced by agents such as thrombin or collagen. Adenine nucleotides act on platelets through three distinct P2 receptors: two are G proteincoupled ADP receptors, namely the P2Y 1 and P2Y 12 receptor subtypes, while the P2X 1 receptor ligand-gated cation channel is activated by ATP. The P2Y 1 receptor initiates platelet aggregation but is not sufficient for a full platelet aggregation in response to ADP, while the P2Y 12 receptor is responsible for completion of the aggregation to ADP. The latter receptor, the molecular target of the antithrombotic drugs clopidogrel, prasugrel and ticagrelor, is responsible for most of the potentiating effects of ADP when platelets are stimulated by agents such as thrombin, collagen or immune complexes. The P2X 1 receptor is involved in platelet shape change and in activation by collagen under shear conditions. Each of these receptors is coupled to specific signal transduction pathways in response to ADP or ATP and is differentially involved in all the sequential events involved in platelet function and haemostasis. As such, they represent potential targets for antithrombotic drugs.

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Section: The P2y 1 Receptor As a Target For New Antiplatelet Compoundsmentioning

confidence: 99%

P2 receptors and platelet function

Hechler

Gachet

2011

Purinergic Signalling

136

127

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“…ADP is known to signal via murine P2Y1, P2Y12, and P2Y13 receptors (48). ADP-induced calcium mobilization was blocked by the P2Y1-selective antagonist MRS 2179, suggesting a predominant involvement of this receptor subtype (2,39).…”

Section: Discussionmentioning

confidence: 96%

Trichinella spiralis Secreted Enzymes Regulate Nucleotide-Induced Mast Cell Activation and Release of Mouse Mast Cell Protease 1

et al. 2012

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Extracellular nucleotides are important triggers of innate immunity, acting on a wide variety of cells via signaling through purinergic receptors. Mucosal mast cells contribute to expulsion of a number of gastrointestinal nematode parasites, and mouse mast cell protease 1 has been shown to have a critical role in clearance of Trichinella spiralis from the intestinal tract. We show here that adenosine, ADP, ATP, UDP, and UTP all stimulate calcium mobilization in bone marrow-derived mast cells with a mucosal phenotype. Secreted proteins from T. spiralis infective larvae inhibit nucleotide-induced mast cell activation, and that induced by ADP and UDP is specifically blocked by parasite secretory 5=-nucleotidase. Release of mouse mast cell protease 1 is stimulated by ADP and ATP. Both parasite secreted products and the 5=-nucleotidase inhibit ADP-induced release of mast cell protease, whereas that stimulated by ATP is partially inhibited by secreted products alone. This indicates that the 5=-nucleotidase contributes to but is not solely responsible for inhibition of nucleotide-mediated effects on mast cell function. Secretion of nucleotide-metabolizing enzymes by parasitic nematodes most likely evolved as a strategy for suppression of innate immune responses and is discussed in this context.

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“…6). For example, the urea derivative 68 is a selective and orally bioavailable antagonist of the human P2Y 1 receptor of novel chemotype with a K i value of 90 nM [122]. Aminobenzazole derivatives from Bristol-Myers Squibb were reported as P2Y 1 receptor antagonists [123].…”

Section: P2y 1 Receptormentioning

confidence: 99%

Pharmacochemistry of the platelet purinergic receptors

Jacobson

Deflorian

Mishra

et al. 2011

Purinergic Signalling

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Platelets contain at least five purinergic G protein-coupled receptors, e.g., the pro-aggregatory P2Y 1 and P2Y 12 receptors, a P2Y 14 receptor (GPR105) of unknown function, and anti-aggregatory A 2A and A 2B adenosine receptor (ARs), in addition to the ligand-gated P2X1 ion channel. Probing the structure-activity relationships (SARs) of the P2X and P2Y receptors for extracellular nucleotides has resulted in numerous new agonist and antagonist ligands. Selective agents derived from known ligands and novel chemotypes can be used to help define the subtypes pharmacologically. Some of these agents have entered into clinical trials in spite of the challenges of drug development for these classes of receptors. The functional architecture of P2 receptors was extensively explored using mutagenesis and molecular modeling, which are useful tools in drug discovery. In general, novel drug delivery methods, prodrug approaches, allosteric modulation, and biased agonism would be desirable to overcome side effects that tend to occur even with receptor subtype-selective ligands. Detailed SAR analyses have been constructed for nucleotide and nonnucleotide ligands at the P2Y 1 , P2Y 12 , and P2Y 14 receptors. The thienopyridine antithrombotic drugs Clopidogrel and Prasugrel require enzymatic pre-activation in vivo and react irreversibly with the P2Y 12 receptor. There is much pharmaceutical development activity aimed at identifying reversible P2Y 12 receptor antagonists. The screening of chemically diverse compound libraries has identified novel chemotypes that act as competitive, non-nucleotide antagonists of the P2Y 1 receptor or the P2Y 12 receptor, and antithrombotic properties of the structurally optimized analogues were demonstrated. In silico screening at the A 2A AR has identified antagonist molecules having novel chemotypes. Fluorescent and other reporter groups incorporated into ligands can enable new technology for receptor assays and imaging. The A 2A agonist CGS21680 and the P2Y 1 receptor antagonist MRS2500 were derivatized for covalent attachment to polyamidoamine dendrimeric carriers of MW 20,000, and the resulting multivalent conjugates inhibited ADP-promoted platelet aggregation. In conclusion, a wide range of new pharmacological tools is available to control platelet function by interacting with cell surface purine receptors.

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P2Y1 receptor antagonists as novel antithrombotic agents

Cited by 45 publications

References 24 publications

P2 receptors and platelet function

P2 receptors and platelet function

Trichinella spiralis Secreted Enzymes Regulate Nucleotide-Induced Mast Cell Activation and Release of Mouse Mast Cell Protease 1

Pharmacochemistry of the platelet purinergic receptors

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