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.
Douglass
James G
JG
Departments of Chemistry, Inspire Pharmaceuticals, Inc., 4222 Emperor Boulevard, Suite 200, Durham, North Carolina 27703-8466, USA. jdouglass@inspirepharm.com
Patel
Roshni I
RI
Yerxa
Benjamin R
BR
Shaver
Sammy R
SR
Watson
Paul S
PS
Bednarski
Krzysztof
K
Plourde
Robert
R
Redick
Catherine C
CC
Brubaker
Kurt
K
Jones
Arthur C
AC
Boyer
José L
JL
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D015226:Dinucleoside Phosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D009711:Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013329:Structure-Activity Relationship
C528858:(6-(6-(3-ethylureido)-9H-purin-9-yl)-2-styryltetrahydrofuro(3,4-d)(1,3)dioxol-4-yl)methyl dihydrogen phosphate; D015226:Dinucleoside Phosphates; D008565:Membrane Proteins; D009711:Nucleotides; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000249:Adenosine Monophosphate; D002118:Calcium