Abstract
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.
MeSH terms
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Adenosine Monophosphate / analogs & derivatives
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Adenosine Monophosphate / chemical synthesis
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Adenosine Monophosphate / chemistry
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Adenosine Monophosphate / pharmacology
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Blood Platelets / metabolism*
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Calcium / metabolism
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Cell Line, Tumor
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Dinucleoside Phosphates / chemical synthesis
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Dinucleoside Phosphates / chemistry
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Dinucleoside Phosphates / pharmacology
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Humans
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In Vitro Techniques
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Membrane Proteins / antagonists & inhibitors*
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Nucleotides / chemical synthesis*
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Nucleotides / chemistry
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Nucleotides / pharmacology
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Platelet Aggregation / drug effects
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Platelet Aggregation Inhibitors / chemical synthesis*
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Platelet Aggregation Inhibitors / chemistry
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Platelet Aggregation Inhibitors / pharmacology
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Purinergic P2 Receptor Antagonists*
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Receptors, Purinergic P2Y12
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Structure-Activity Relationship
Substances
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(6-(6-(3-ethylureido)-9H-purin-9-yl)-2-styryltetrahydrofuro(3,4-d)(1,3)dioxol-4-yl)methyl dihydrogen phosphate
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Dinucleoside Phosphates
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Membrane Proteins
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Nucleotides
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P2RY12 protein, human
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Platelet Aggregation Inhibitors
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Purinergic P2 Receptor Antagonists
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Receptors, Purinergic P2Y12
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Adenosine Monophosphate
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Calcium