Carba-nucleosides as Potent Antagonists of the Adenosine 5′-Diphosphate (ADP) Purinergic Receptor (P2Y12) on Human Platelets
| Autor: | Tom Jay Parry, Bruce P. Damiano, Hong Ye, Barbara J. Haertlein, Cailin Chen, Bruce E. Maryanoff, Han-Cheng Zhang |
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| Rok vydání: | 2008 |
| Předmět: |
Blood Platelets
P2Y receptor Platelet Aggregation medicine.drug_class Tetrazoles Pharmacology Biochemistry chemistry.chemical_compound P2Y12 Cangrelor Drug Discovery Purinergic P2 Receptor Antagonists medicine Humans Platelet Platelet activation General Pharmacology Toxicology and Pharmaceutics Receptors Purinergic P2 Chemistry Organic Chemistry Nucleosides Adenosine A3 receptor Receptor antagonist Receptors Purinergic P2Y12 GTP-Binding Protein alpha Subunits Gq-G11 Molecular Medicine Calcium Adenosine A2B receptor Signal Transduction |
| Zdroj: | ChemMedChem. 3:732-736 |
| ISSN: | 1860-7187 1860-7179 |
| DOI: | 10.1002/cmdc.200700310 |
| Popis: | Whereas the activation and aggregation of blood platelets are crucial to normal hemostasis, this ensemble is also a key factor in serious cardiovascular disorders, such as myocardial infarction, unstable angina, transient ischemic attack, stroke, peripheral arterial disease, and artherosclerosis. Indeed, abnormal thrombosis is a root cause of adverse cardiovascular events that are responsible for death and disability in humans. As a consequence, plate ACHTUNGTRENNUNGlets are targeted by clinically useful antithrombotic drugs, such as the cyclooxygenase-1 inhibitor aspirin, the GPIIb/IIIa antagonist abciximab, and the adenosine 5’-diphosphate (ADP) receptor antagonist clopidogrel. ADP is an important agonist of platelet activation and aggregation because it induces platelet shape change accompanied by the activation of fibrinogen receptors (GPIIb/IIIa). On platelets, there are three types of cell-surface receptors for ADP, which are members of the P2 purinergic class: P2X1, P2Y1, and P2Y12. [4, 5] P2Y1 and P2Y12 are G protein-coupled receptors (GPCRs), whereas P2X1 is a ligand-gated ion channel. The Gqcoupled P2Y1 receptor initiates ADP-induced platelet activation and the Gi-coupled P2Y12 receptor amplifies activation processes, including aggregation, granule secretion, and procoagulant activity, as caused by various agonists. From this perspective, antagonists of P2Y12 can be therapeutically effective by markedly inhibiting platelet function independent of the activating stimulus. Additionally, because of the restricted distribution of P2Y12 in humans, this receptor is an attractive antiplatelet target for drug discovery. The widespread clinical use of clopidogrel has demonstrated the relevance of inhibiting the platelet-specific P2Y12 receptor to prevent untoward cardiovascular events. However, clopidogrel is a prodrug that requires metabolic conversion in vivo to a highly unstable, reactive species that covalently modifies the P2Y12 receptor. [7] On account of this property, there have been observations in humans of slow onset of pharmacological action and of high interpatient variability. Thus, drug discovery efforts have been mounted to identify potent, direct acting, reversible P2Y12 antagonists, and some promising compounds have emerged, including Cangrelor (AR-C69931MX), AZD-6140, and PRT-128. In seeking suitable drug candidates in this area, we have been exploring carba-nucleoside derivatives that are structurally related to AZD-6140 as reversible P2Y12 antagonists. In this paper, we report on the synthesis and biological evaluation of novel compounds, including tetrazole-containing derivatives with high receptor affinity and excellent potency for inhibiting P2Y12-mediated effects on human platelets. |
| Databáze: | OpenAIRE |
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