Antagonists of the platelet P2T receptor: a novel approach to antithrombotic therapy
| Autor: | Simon F. Hunt, Jane A. Clegg, Barry Teobald, Paul Willis, David Cox, Andrew Bailey, James A. Smith, John Dixon, Wendy Tomlinson, Mandy E. Coombs, P. Leff, R.G. Humphries, Anthony Ingall, Nicholas Kindon, Judith I. McInally |
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| Rok vydání: | 1999 |
| Předmět: |
Agonist
Blood Platelets Magnetic Resonance Spectroscopy medicine.drug_class Pharmacology P2 receptor Spectrometry Mass Fast Atom Bombardment chemistry.chemical_compound Drug Discovery Antithrombotic medicine Purinergic P2 Receptor Antagonists Humans Platelet Receptor Molecular Structure Membrane Proteins Thrombosis Receptor antagonist Adenosine Monophosphate Receptors Purinergic P2Y12 Adenosine diphosphate Biochemistry chemistry Competitive antagonist Molecular Medicine Platelet Aggregation Inhibitors |
| Zdroj: | Journal of medicinal chemistry. 42(2) |
| ISSN: | 0022-2623 |
| Popis: | The platelet P2T receptor plays a major role in platelet aggregation, and its antagonists are predicted to have significant therapeutic potential as antithrombotic agents. We have explored analogues of adenosine triphosphate (ATP), which is a weak, nonselective but competitive P2T receptor antagonist. Modification of the polyphosphate side chain to prevent breakdown to the agonist adenosine diphosphate (ADP) and substitution of the adenine moiety to enhance affinity and selectivity for the P2T receptor led to the identification of 10e (AR-C67085MX), having an IC50 of 2.5 nM against ADP-induced aggregation of human platelets. Compound 10e was the first very potent antagonist of the P2T receptor, with a selectivity for that subtype of the P2 receptor family of >1000-fold. Further modification of the structure produced compound 10l (AR-C69931MX) having an IC50 of 0.4 nM. In vivo, at maximally effective antithrombotic doses, there is little prolongation of bleeding time (1.4-fold), which is in marked contrast to the 5-6-fold found with GPIIb/IIIa antagonists. |
| Databáze: | OpenAIRE |
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