title: Rapid and reversible modulation of platelet function in man by a novel P2Y(12) ADP-receptor antagonist, INS50589.
abstract: P2Y(12) receptors participate in ADP-induced activation and aggregation of human platelets. INS50589, a selective P2Y(12) receptor antagonist, is being developed for use where controlled, reversible modulation of the platelet hemostatic function is needed. The tolerability, pharmacokinetics, and pharmacodynamics of INS50589 were tested in healthy human volunteers. Thirty-six subjects received intravenous infusions of placebo or INS50589 at 0.1-3 mg/kg/h for four hours. Platelet function, clotting parameters, bleeding time, safety assessments, and plasma concentrations of INS50589 and its major metabolite were monitored for 24 hours. Near-steady state plasma concentrations of INS50589 and effects on platelet function were achieved rapidly. The average maximal plasma concentration of INS50589 was linearly related to the dose administered. Intravenous INS50589 produced dose-dependent inhibition of platelet activation and aggregation in response to ADP in vitro until nearly full inhibition was achieved at the higher doses. Bleeding time was correspondingly increased, without any effect on activated clotting time, prothrombin time, or activated partial thromboplastin time. Platelet response to ADP had returned to at least 75% of the baseline value within 0.25-4 h after cessation of the intravenous infusion of INS50589, depending upon the dose and ADP challenge concentration. Infusions were well tolerated up to the highest dose tested. There was no evidence that the principal metabolite (INS51088) contributed to these effects. INS50589 is a well-tolerated, reversible, competitive antagonist of ADP at the P2Y(12) human platelet receptor, and its potential therapeutic utility in various cardiovascular settings is discussed.
authors.affiliation: Inspire Pharmaceuticals Inc., 4222 Emperor Blvd Suite 200, Durham, NC 27703-8030, USA. fjohnson@inspirepharm.com
authors.forename: Fred L
authors.initials: FL
authors.lastname: Johnson
authors.forename: José L
authors.initials: JL
authors.lastname: Boyer
authors.forename: Philip T
authors.initials: PT
authors.lastname: Leese
authors.forename: Christopher
authors.initials: C
authors.lastname: Crean
authors.forename: Ramesh
authors.initials: R
authors.lastname: Krishnamoorthy
authors.forename: Todd
authors.initials: T
authors.lastname: Durham
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Fox
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Kellerman
mesh_terms: D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors*; D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D000293:Adolescent; D000328:Adult; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism*; D002318:Cardiovascular Diseases; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011517:Prothrombin Time; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12
chemical_list: C523638:INS 50589; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate