Circulation, Vol 88, 1512-1517, Copyright © 1993 by American Heart Association
K Peerlinck, I De Lepeleire, M Goldberg, D Farrell, J Barrett, E Hand, D Panebianco, H Deckmyn, J Vermylen and J Arnout
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 microgram.kg-1 x 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 microgram.kg-1 x 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 microgram.kg-1 x min-1), and five
received placebo. Complete inhibition of ex vivo platelet aggregation was
seen at 0.15 and 0.2 microgram.kg-1 x min-1. At 0.2 microgram.kg-1 x 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.
ARTICLES
MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man
Center for Molecular and Vascular Biology, University of Leuven, Belgium.
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