Rapid and reversible modulation of platelet function in man by a novel P2Y12 ADP-receptor antagonist, INS50589

被引:13
|
作者
Johnson, Fred L.
Boyer, Jose L.
Leese, Philip T.
Crean, Christopher
Krishnamoorthy, Ramesh
Durham, Todd
Fox, Anthony W.
Kellerman, Donald J.
机构
[1] Inpire Pharmaceut Inc, Durham, NC 27703 USA
[2] Quintiles Phase One Serv Inc, Lenexa, KS 66219 USA
[3] EBD Grp, Carlsbad, CA 92011 USA
关键词
P2Y12; receptor; ADP receptor; percutaneous coronary intervention; cardiopulmonary bypass; clinical trial; pharmacodynamics;
D O I
10.1080/09537100701268741
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:346 / 356
页数:11
相关论文
共 50 条
  • [31] The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration
    Baumann, Martine
    Lack, Benoit
    Guillaumat, Isabelle
    Murphy, Mark J.
    Riederer, Markus A.
    PLATELETS, 2022, 33 (01) : 147 - 156
  • [32] Novel Platelet ADP P2Y12 Inhibitors in the Treatment of Acute Coronary Syndrome
    Tan, Guang-Ming
    Lam, Yat-Yin
    Yan, Bryan P.
    CARDIOVASCULAR THERAPEUTICS, 2012, 30 (04) : e167 - e173
  • [33] Novel tricyclic benzothiazolo[2,3-c]thiadiazine antagonists of the platelet ADP receptor (P2Y12)
    Scarborough, RM
    Laibelman, AM
    Clizbe, LA
    Fretto, LJ
    Conley, PB
    Reynolds, EE
    Sedlock, DM
    Jantzen, HM
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (14) : 1805 - 1808
  • [34] Variability of antiaggregant response to clopidogrel in healthy subjects:: First correlation to platelet P2Y12 ADP-receptor occupancy in 3 selected platelet-response groups
    Drouet, Ludovic
    Sollier, Claire Bal dit
    Hovsepian, Lionel
    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2007, 49 (09) : 376A - 376A
  • [35] Pharmacology and potential role of selatogrel, a subcutaneous platelet P2Y12 receptor antagonist
    Parker, William A. E.
    Storey, Robert F.
    EXPERT OPINION ON EMERGING DRUGS, 2020, 25 (01) : 1 - 6
  • [36] The P2Y12 Receptor Antagonist Selatogrel Dissolves Preformed Platelet Thrombi In Vivo
    Crescence, Lydie
    Kramberg, Markus
    Baumann, Martine
    Rey, Markus
    Roux, Sebastien
    Panicot-Dubois, Laurence
    Dubois, Christophe
    Riederer, Markus A.
    JOURNAL OF CLINICAL MEDICINE, 2021, 10 (22)
  • [37] Gi-dependent and -independent mechanisms downstream of the P2Y12 ADP-receptor (vol 2, pg 135, 2004)
    Soulet, C
    Sauzeau, V
    Plantavid, M
    Herbert, JM
    Pacaud, P
    Payrastre, P
    Savi, P
    JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2004, 2 (06) : 1027 - 1027
  • [38] Role of ADP receptor P2Y12 in platelet adhesion and thrombus formation in flowing blood
    Remijn, JA
    Wu, YP
    Jeninga, EH
    Ijsseldijk, MJW
    van Willigen, G
    de Groot, PG
    Sixma, JJ
    Nurden, AT
    Nurden, P
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2002, 22 (04) : 686 - 691
  • [39] Biology and pharmacology of the platelet P2Y12 receptor
    Storey, Robert F.
    CURRENT PHARMACEUTICAL DESIGN, 2006, 12 (10) : 1255 - 1259
  • [40] Mechanism of action and clinical development of ticagrelor, a novel platelet ADP P2Y(12) receptor antagonist
    Capodanno, Davide
    Dharmashankar, Kodlipet
    Angiolillo, Dominick J.
    EXPERT REVIEW OF CARDIOVASCULAR THERAPY, 2010, 8 (02) : 151 - 158