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

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

Research output: Contribution to journalArticle

157 Citations (Scopus)

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-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

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

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tirofiban
Integrin beta3
Platelet Glycoprotein GPIIb-IIIa Complex
Platelet Aggregation
Bleeding Time
Fibrinogen
Placebos
Blood Platelets
Fibrinolytic Agents
Intravenous Infusions
Adenosine Diphosphate
Inhibitory Concentration 50
Tyrosine
Healthy Volunteers
Collagen

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Peerlinck, K., De Lepeleire, I., Goldberg, M., Farrell, D., Barrett, J., Hand, E., ... 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.

MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man. / Peerlinck, K.; De Lepeleire, I.; Goldberg, M.; Farrell, David; Barrett, J.; Hand, E.; Panebianco, D.; Deckmyn, H.; Vermylen, J.; Arnout, J.

In: Circulation, Vol. 88, No. 4, 10.1993, p. 1512-1517.

Research output: Contribution to journalArticle

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, vol. 88, no. 4, pp. 1512-1517.
Peerlinck K, De Lepeleire I, Goldberg M, Farrell D, Barrett J, Hand E et al. MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man. Circulation. 1993 Oct;88(4):1512-1517.
Peerlinck, K. ; De Lepeleire, I. ; Goldberg, M. ; Farrell, David ; Barrett, J. ; Hand, E. ; Panebianco, D. ; Deckmyn, H. ; Vermylen, J. ; Arnout, J. / MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man. In: Circulation. 1993 ; Vol. 88, No. 4. pp. 1512-1517.
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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-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",
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AU - Goldberg, M.

AU - Farrell, David

AU - Barrett, J.

AU - Hand, E.

AU - Panebianco, D.

AU - Deckmyn, H.

AU - Vermylen, J.

AU - Arnout, J.

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