title: 6-Amino-2-mercapto-3H-pyrimidin-4-one derivatives as new candidates for the antagonism at the P2Y12 receptors.
abstract: P2Y(12) plays an important role in platelet aggregation, which makes it an interesting target for antithrombotic agents. Compounds that antagonize P2Y(12) include the active metabolites of thienopyridines and molecules that are structurally related to ATP, which is an antagonist of P2Y(12). During the last few years, our group has been working on the development of P2Y(12) receptors antagonists that are based on an extremely simple chemical structure, the 6-amino-2-mercapto-3H-pyrimidin-4-one, variously substituted at the sulfur and oxygen functions. This nucleus represents the simplified combination of two known P2Y(12) antagonists: the active metabolite of the thienopyridines and ATP derivatives. The effects of the synthesized compounds were tested on ADP-induced human platelet aggregation, using light transmission aggregometry. None of the tested compounds induced platelet aggregation, while some of them, at concentration of 10(-4)M, partially inhibited platelet aggregation induced by ADP 10(-6)M. The most potent compound, 6b, antagonized the inhibitory effect of 2-methylthio-ADP on the forskolin-induced accumulation of cyclic-AMP in CHO FlpIN cells expressing recombinant human P2Y(12)-receptors. In addition, none of the tested compounds, including 6b, interfered with ligand binding to P1 receptors. Our results suggest that some of the synthesized compounds are specific antagonists of P2 receptors, and in particular of P2Y(12) and suggest that further development of this structurally new series of compounds as P2Y(12) receptors antagonists is recommended.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Ferrara, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Crepaldi
authors.forename: Barbara
authors.initials: B
authors.lastname: Cacciari
authors.forename: Maria-Cruz
authors.initials: MC
authors.lastname: Bonache
authors.forename: Giampiero
authors.initials: G
authors.lastname: Spalluto
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Ivar von
authors.initials: Iv
authors.lastname: Kügelgen
authors.forename: Kristina
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Pugliano
authors.forename: Cristina
authors.initials: C
authors.lastname: Razzari
authors.forename: Marco
authors.initials: M
authors.lastname: Cattaneo
mesh_terms: D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects*; D010979:Platelet Function Tests; D011485:Protein Binding; D058919:Purinergic P2 Receptor Antagonists; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology*; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C548576:P2RY12 protein, human; D058919:Purinergic P2 Receptor Antagonists; D011744:Pyrimidinones; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D011994:Recombinant Proteins; D013438:Sulfhydryl Compounds; D000242:Cyclic AMP