Lipophilic modifications to dinucleoside polyphosphates and nucleotides that confer antagonist properties at the platelet P2Y(12) receptor

Platelet P2Y(12) 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 an...

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Published inJournal 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, Jose L.
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 28.02.2008
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
CLOPIDOGREL
FLUORESCENT ANALOGS
PHARMACOLOGY
BIOLOGICAL-ACTIVITY
TRIPHOSPHATE
DIADENOSINE 5,5-P-1,P-4-TETRAPHOSPHATE
TETRAPHOSPHATE
IDENTIFICATION
ATP
AGGREGATION
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Summary:Platelet P2Y(12) 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm701348d