DG-041 inhibits the EP3 prostanoid receptor—A new target for inhibition of platelet function in atherothrombotic disease

Autor:	Stan Heptinstall, David Iyu Espinosa, Natalia Dovlatova, Jackie R. Glenn, Ann E. White, Panagiotis Manolopoulos, David Hermann, Andrew D. Johnson, Kari Stefansson, Olafur T. Magnusson, Dan Hartman, Jane A. May, Susan C. Fox, Mark E. Gurney
Rok vydání:	2008
Předmět:	Blood Platelets Agonist medicine.medical_specialty Platelet Aggregation medicine.drug_class Dinoprostone chemistry.chemical_compound Internal medicine Purinergic P2 Receptor Antagonists medicine Humans Receptors Prostaglandin E Drug Interactions Platelet Sulfones Prostaglandin E2 Receptor Cells Cultured Acrylamides Aspirin Platelet-activating factor Antagonist Prostanoid Hematology General Medicine Atherosclerosis Adenosine Monophosphate Receptors Purinergic P2Y12 Adenosine diphosphate Endocrinology chemistry Receptors Prostaglandin E EP3 Subtype lipids (amino acids peptides and proteins) Platelet Aggregation Inhibitors medicine.drug
Zdroj:	Platelets. 19:605-613
ISSN:	1369-1635 0953-7104
DOI:	10.1080/09537100802351073
Popis:	Receptors for prostanoids on platelets include the EP3 receptor for which the natural agonist is the inflammatory mediator prostaglandin E(2) (PGE(2)) produced in atherosclerotic plaques. EP3 is implicated in atherothrombosis and an EP3 antagonist might provide atherosclerotic lesion-specific antithrombotic therapy. DG-041 (2,3-dichlorothiophene-5-sulfonic acid, 3-[1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]acryloylamide) is a direct-acting EP3 antagonist currently being evaluated in Phase 2 clinical trials. We have examined the contributions of EP3 to platelet function using the selective EP3 agonist sulprostone and also PGE(2), and determined the effects of DG-041 on these. Studies were in human platelet-rich plasma or whole blood and included aggregometry and flow cytometry. Sulprostone enhanced aggregation induced by primary agonists including collagen, TRAP, platelet activating factor, U46619, serotonin and adenosine diphosphate, and enhanced P-selectin expression and platelet-leukocyte conjugate formation. It inhibited adenylate cyclase (measured by vasodilator-stimulated phosphoprotein phosphorylation) and enhanced Ca(2+) mobilization. It potentiated platelet function even in the presence of aspirin and/or AR-C69931 (a P2Y(12) antagonist). DG-041 antagonized the effects of sulprostone on platelet function. The effect of PGE(2) on platelet aggregation depended on the nature of the agonist and the concentration of PGE(2) used as a consequence of both pro-aggregatory effects via EP3 and anti-aggregatory effects via other receptors. DG-041 potentiated the protective effects of PGE(2) on platelet aggregation by inhibiting the pro-aggregatory effect via EP3 stimulation. DG-041 remained effective in the presence of a P2Y(12) antagonist and aspirin. DG-041 warrants continued investigation as a potential agent for the treatment of atherothrombosis without inducing unwanted bleeding risk.
Databáze:	OpenAIRE
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