MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man

K. Peerlinck, I. De Lepeleire, M. Goldberg, D. Farrell, J. Barrett, E. Hand, D. Panebianco, H. Deckmyn, J. Vermylen, J. Arnout

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Abstract

Background. Fibrinogen-dependent cross-linking of glycoprotein (GP) IIb/IIIa on activated platelets is the final mechanism leading to platelet aggregation. Inhibition of this mechanism may result in a novel antithrombotic agent. We studied the activity of MK-383 (L-700,462), a new, nonpeptide GPIIb/IIIa antagonist, in vitro and in vivo, in man. Methods and Results. MK-383, a nonpeptide tyrosine derivative, dose-dependently inhibited fibrinogen-dependent platelet aggregation, in vitro. Binding of 125I-labeled fibrinogen to activated platelets was prevented in a competitive manner with an IC50 of 10±4.2 nmol/L. The activity and tolerability of MK-383 were evaluated in a two-part double-blind, placebo-controlled, dose-escalation study in healthy male subjects using 1- and 4-hour intravenous infusions. Effects on ADP- and collagen-induced ex vivo platelet aggregation (APA or CPA) and template bleeding time (TBT) were evaluated. Twenty-four subjects participated in the 1-hour part. Six received placebo and 18 MK-383 in doses ranging from 0.05 to 0.40 μg · kg-1 · min-1. MK-383 inhibited platelet aggregation and prolonged bleeding time in a dose-dependent manner. APA and CPA were totally inhibited at the end of infusion of 0.4 μg · kg-1 · min-1 and returned to 55% and 89% of baseline, respectively, at 3 hours after infusion. TBT was prolonged at this dose from 5.0±1.3 minutes predose to 22.7±6 minutes at the end of the infusion (P<.01) and was normalized by 3 hours after infusion. In the 4-hour infusion part, 15 subjects received MK-383 (0.1 to 0.2 μg · kg-1 · min-1, and five received placebo. Complete inhibition of ex vivo platelet aggregation was seen at 0.15 and 0.2 μg · kg-1 · min-1. At 0.2 μg · kg-1 · min-1, TBT was prolonged from 4.4±1.2 to 23.9+4.3 minutes at the end of infusion (P<.01) and remained slightly prolonged 3 hours after infusion (7.2±1.8 minutes). No adverse effects were observed in any of the 33 subjects receiving MK-383. Conclusions. The results from this study indicate that MK-383 appears to be well tolerated and active in man. It is the first nonpeptide GPIIb/IIIa antagonist that can be used to investigate the antithrombotic potential of this new class of antiplatelet agents.

Original languageEnglish (US)
Pages (from-to)1512-1517
Number of pages6
JournalCirculation
Volume88
Issue number4
DOIs
StatePublished - Oct 1993

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Keywords

  • Antihrombotic drug
  • Antiplatelet agents
  • Bleeding time
  • Fibrinogen receptor
  • Integrin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Peerlinck, K., De Lepeleire, I., Goldberg, M., Farrell, D., Barrett, J., Hand, E., Panebianco, D., Deckmyn, H., Vermylen, J., & Arnout, J. (1993). MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man. Circulation, 88(4), 1512-1517. https://doi.org/10.1161/01.CIR.88.4.1512