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Antiplatelet Activity, P2Y1 and P2Y12 Inhibition, and Metabolism in Plasma of Stereoisomers of Diadenosine 5′,5′″-P1,P4-dithio-P2,P3-chloromethylenetetraphosphate.
- Source :
- PLoS ONE; Apr2014, Vol. 9 Issue 4, p1-8, 8p
- Publication Year :
- 2014
-
Abstract
- Background: Diadenosine tetraphosphate (Ap<subscript>4</subscript>A), a constituent of platelet dense granules, and its P<superscript>1</superscript>,P<superscript>4</superscript>-dithio and/or P<superscript>2</superscript>,P<superscript>3</superscript>-chloromethylene analogs, inhibit adenosine diphosphate (ADP)-induced platelet aggregation. We recently reported that these compounds antagonize both platelet ADP receptors, P2Y<subscript>1</subscript> and P2Y<subscript>12</subscript>. The most active of those analogs, diadenosine 5′,5″″-P<superscript>1</superscript>,P<superscript>4</superscript>-dithio-P<superscript>2</superscript>,P<superscript>3</superscript>-chloromethylenetetraphosphate, (compound 1), exists as a mixture of 4 stereoisomers. Objective: To separate the stereoisomers of compound 1 and determine their effects on platelet aggregation, platelet P2Y<subscript>1</subscript> and P2Y<subscript>12</subscript> receptor antagonism, and their metabolism in human plasma. Methods: We separated the 4 diastereomers of compound 1 by preparative reversed-phase chromatography, and studied their effect on ADP-induced platelet aggregation, P2Y<subscript>1</subscript>-mediated changes in cytosolic Ca<superscript>2+</superscript>, P2Y<subscript>12</subscript>-mediated changes in VASP phosphorylation, and metabolism in human plasma. Results: The inhibition of ADP-induced human platelet aggregation and human platelet P2Y<subscript>12</subscript> receptor, and stability in human plasma strongly depended on the stereo-configuration of the chiral P<superscript>1</superscript>- and P<superscript>4</superscript>-phosphorothioate groups, the S<subscript>P</subscript>S<subscript>P</subscript> diastereomer being the most potent inhibitor and completely resistant to degradation in plasma, and the R<subscript>P</subscript>R<subscript>P</subscript> diastereomer being the least potent inhibitor and with the lowest plasma stability. The inhibitory activity of S<subscript>P</subscript>R<subscript>P</subscript> diastereomers depended on the configuration of the pseudo-asymmetric carbon of the P<superscript>2</superscript>,P<superscript>3</superscript>-chloromethylene group, one of the configurations being significantly more active than the other. Their plasma stability did not differ significantly, being intermediate to that of the S<subscript>P</subscript>S<subscript>P</subscript> and the R<subscript>P</subscript>R<subscript>P</subscript> diastereomers. Conclusions: The presently-described stereoisomers have utility for structural, mechanistic, and drug development studies of dual antagonists of platelet P2Y<subscript>1</subscript> and P2Y<subscript>12</subscript> receptors. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 9
- Issue :
- 4
- Database :
- Complementary Index
- Journal :
- PLoS ONE
- Publication Type :
- Academic Journal
- Accession number :
- 95819325
- Full Text :
- https://doi.org/10.1371/journal.pone.0094780