Paul S. Watson

Lipophilic Modifications to Dinucleoside Polyphosphates and Nucleotides that Confer Antagonist Properties at the Platelet P2Y12 Receptor

Platelet P2Y12 receptors play a central role in the regulation of platelet function and inhibition of this receptor by treatment with drugs such as clopidogrel results in a reduction of atherothrombotic events. We discovered that modification of natural and synthetic dinucleoside polyphosphates and nucleotides with lipophilic substituents on the ribose and base conferred P2Y12 receptor antagonist properties to these molecules producing potent inhibitors of ADP-mediated platelet aggregation. We describe methods for the preparation of these functionalized dinucleoside polyphosphates and nucleotides and report their associated activities. By analysis of these results and by deconstruction of the necessary structural elements through selected syntheses, we prepared a series of highly functionalized nucleotides, resulting in the selection of an adenosine monophosphate derivative (62) for further clinical development.

Adenosine analogues as inhibitors of P2Y12 receptor mediated platelet aggregation

Modified adenosine derivatives may lead to the development of P2Y(12) antagonists that are potent, selective, and bind reversibly to the receptor. Analogues of 2,3-trans-styryl acetal-N6-ureido-adenosine monophosphate were prepared by modification of the 5-position. The resulting analogues were tested for P2Y(12) antagonism in a platelet aggregation assay.