Antagonists of the Platelet P 2T Receptor:  A Novel Approach to Antithrombotic Therapy

• Published in: Journal of medicinal chemistry Vol. 42; no. 2; pp. 213 - 220
• Main Authors: Ingall, Anthony H, Dixon, John, Bailey, Andrew, Coombs, Mandy E, Cox, David, McInally, Judith I, Hunt, Simon F, Kindon, Nicholas D, Teobald, Barry J, Willis, Paul A, Humphries, Robert G, Leff, Paul, Clegg, Jane A, Smith, James A, Tomlinson, Wendy
• Format: Journal Article
• Language: English
• Published: American Chemical Society 28-01-1999
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm981072s

The platelet P 2T 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 P 2T 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 P 2T 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 P 2T 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.