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

• Published in: Journal of medicinal chemistry Vol. 51; no. 4; pp. 1007 - 1025
• Main Authors: Douglass, James G, Patel, Roshni I, Yerxa, Benjamin R, Shaver, Sammy R, Watson, Paul S, Bednarski, Krzysztof, Plourde, Robert, Redick, Catherine C, Brubaker, Kurt, Jones, Arthur C, Boyer, José L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 28.02.2008
• Subjects: Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - chemical synthesis; Adenosine Monophosphate - chemistry; Adenosine Monophosphate - pharmacology; Biological and medical sciences; Blood Platelets - metabolism; Blood. Blood coagulation. Reticuloendothelial system; Calcium - metabolism; Cell Line, Tumor; Dinucleoside Phosphates - chemical synthesis; Dinucleoside Phosphates - chemistry; Dinucleoside Phosphates - pharmacology; Humans; In Vitro Techniques; Medical sciences; Membrane Proteins - antagonists & inhibitors; Nucleotides - chemical synthesis; Nucleotides - chemistry; Nucleotides - pharmacology; Pharmacology. Drug treatments; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - chemistry; Platelet Aggregation Inhibitors - pharmacology; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Structure-Activity Relationship; Purine nucleotide; P2Y12 purinergic receptor; Dinucleotide; Anticoagulant; In vitro; Polyphosphates; Antiplatelet agent; Lipophilic compound; Platelet; Structure activity relation; Nucleotide; Clopidogrel; Ureas; Antagonist; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm701348d

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.