title: Novel P2Y12 adenosine diphosphate receptor antagonists for inhibition of platelet aggregation (I): in vitro effects on platelets.
abstract: ADP plays a key role in platelet aggregation which has led to the development of antiplatelet drugs that target the P2Y12 receptor. The aim of this study was to characterize the effects of two novel P2Y12 receptor antagonists, BX 667 and its active metabolite BX 048, on platelets. BX 667 and BX 048 block the binding of 2MeSADP to platelets and antagonize ADP-induced platelet aggregation in human, dog and rat washed platelets. Both compounds were shown to be reversible inhibitors of platelet aggregation. BX 048 prevents the decrease in cAMP induced by treatment of platelets with ADP. The specificity of BX 667 and BX 048 was demonstrated against cell lines expressing P2Y1 and P2Y6 as well as against a panel of receptors and enzymes. Taken all together these data show that both BX 048 and BX 667 are potent P2Y12 antagonists with high specificity which, in the accompanying paper are demonstrated to behave predictably in vivo.
authors.affiliation: Berlex Biosciences, Richmond, CA 94804, USA.
authors.forename: Judi
authors.initials: J
authors.lastname: Bryant
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Post
authors.forename: Serene
authors.initials: S
authors.lastname: Alexander
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Wang
authors.forename: Lorraine
authors.initials: L
authors.lastname: Kent
authors.forename: Sabine
authors.initials: S
authors.lastname: Schirm
authors.forename: Jih-Lie
authors.initials: JL
authors.lastname: Tseng
authors.forename: Babu
authors.initials: B
authors.lastname: Subramanyam
authors.forename: Brad
authors.initials: B
authors.lastname: Buckman
authors.forename: Imadul
authors.initials: I
authors.lastname: Islam
authors.forename: Shendong
authors.initials: S
authors.lastname: Yuan
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sullivan
authors.forename: Mike
authors.initials: M
authors.lastname: Snider
authors.forename: John
authors.initials: J
authors.lastname: Morser
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D007651:Keto Acids / Q000494:pharmacology*; D008024:Ligands; D008954:Models, Biological; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011485:Protein Binding; D058919:Purinergic P2 Receptor Antagonists; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12; D013045:Species Specificity
chemical_list: C533036:4-(((4-(1-carboxy-1-methylethoxy)-7-methylquinolin-2-yl)carbonyl)amino)-5-(4-(ethoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid; C533035:4-((4-(1-(ethoxycarbonyl)-1-methylethoxy)-7-methyl-2-quinolyl)carbamoyl)-5-(4-(ethoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid; D007651:Keto Acids; D008024:Ligands; C548576:P2RY12 protein, human; C553058:P2ry12 protein, rat; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D011804:Quinolines; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D002118:Calcium