title: MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man.
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.
  
  
  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.
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Peerlinck
authors.forename: I
authors.initials: I
authors.lastname: De Lepeleire
authors.forename: M
authors.initials: M
authors.lastname: Goldberg
authors.forename: D
authors.initials: D
authors.lastname: Farrell
authors.forename: J
authors.initials: J
authors.lastname: Barrett
authors.forename: E
authors.initials: E
authors.lastname: Hand
authors.forename: D
authors.initials: D
authors.lastname: Panebianco
authors.forename: H
authors.initials: H
authors.lastname: Deckmyn
authors.forename: J
authors.initials: J
authors.lastname: Vermylen
authors.forename: J
authors.initials: J
authors.lastname: Arnout
mesh_terms: D001760:Bleeding Time; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D000077466:Tirofiban; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D014443:Tyrosine; D000077466:Tirofiban