Novel P2Y12 adenosine diphosphate receptor antagonists for inhibition of platelet aggregation (II): pharmacodynamic and pharmacokinetic characterization.
Antiplatelet drugs are used to prevent aberrant platelet activation in pathophysiologic conditions such as myocardial infarction and ischemic stroke. The key role that ADP plays in this process has led to the development of antiplatelet drugs that target the P2Y12 receptor. The aim of this study was to characterize the pharmacodynamic (PD) and pharmacokinetic (PK) properties of the novel P2Y12 receptor antagonists, BX 667 and BX 048. BX 667 blocks ADP-induced platelet aggregation in human, dog and rat blood (IC50=97, 317 and 3000 nM respectively). BX 667 had nominal effects on collagen-induced aggregation and weakly inhibited arachidonic acid-induced aggregation. BX 667 has an active metabolite, BX 048, that also potently inhibits ADP-induced aggregation (IC50=290 nM) in human blood. BX 667 was shown to have high oral bioavailability in both dog and rat unlike BX 048. Administration of BX 667 resulted in a rapid and sustained inhibition of platelet aggregation where the extent and duration of platelet inhibition was directly proportional to circulating plasma levels. This report describes the PK/PD properties of BX 667 showing that it has the properties required for a potential antiplatelet therapeutic agent.
Berlex Biosciences, Richmond, CA 94804, USA.
Joseph M
JM
Post
Serene
S
Alexander
Yi-Xin
YX
Wang
Jon
J
Vincelette
Ron
R
Vergona
Lorraine
L
Kent
Judi
J
Bryant
Mark E
ME
Sullivan
William P
WP
Dole
John
J
Morser
Babu
B
Subramanyam
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007651:Keto Acids / Q000493:pharmacokinetics*; D008024:Ligands; D008297:Male; D008954:Models, Biological; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D011485:Protein Binding; D058919:Purinergic P2 Receptor Antagonists; D011804:Quinolines / Q000493:pharmacokinetics*; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12; D013045:Species Specificity
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