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Title: MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man
Authors: Peerlinck, Kathelijne ×
De Lepeleire, I
Goldberg, M
Farrell, D
Barrett, J
Hand, E
Panebianco, D
Deckmyn, Hans
Vermylen, Jozef
Arnout, Jozef #
Issue Date: Nov-1993
Series Title: Circulation vol:88 issue:4 Pt 1 pages:1512-7
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 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.
ISSN: 0009-7322
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular and Vascular Biology
Chemistry, Campus Kulak Kortrijk
Interdisciplinary Research Facility Life Sciences, Campus Kulak Kortrijk
Biomedical Sciences Group Management - miscellaneous
Faculty of Medicine - miscellaneous
× corresponding author
# (joint) last author

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