title: Lipophilic modifications to dinucleoside polyphosphates and nucleotides that confer antagonist properties at the platelet P2Y12 receptor.
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.
authors.affiliation: Departments of Chemistry, Inspire Pharmaceuticals, Inc., 4222 Emperor Boulevard, Suite 200, Durham, North Carolina 27703-8466, USA. jdouglass@inspirepharm.com
authors.forename: James G
authors.initials: JG
authors.lastname: Douglass
authors.forename: Roshni I
authors.initials: RI
authors.lastname: Patel
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Yerxa
authors.forename: Sammy R
authors.initials: SR
authors.lastname: Shaver
authors.forename: Paul S
authors.initials: PS
authors.lastname: Watson
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Bednarski
authors.forename: Robert
authors.initials: R
authors.lastname: Plourde
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Redick
authors.forename: Kurt
authors.initials: K
authors.lastname: Brubaker
authors.forename: Arthur C
authors.initials: AC
authors.lastname: Jones
authors.forename: José L
authors.initials: JL
authors.lastname: Boyer
mesh_terms: 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
chemical_list: 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