MK-383 (L-700,462), A SELECTIVE NONPEPTIDE PLATELET GLYCOPROTEIN-IIB IIIA ANTAGONIST, IS ACTIVE IN MAN/

Background. Fibrinogen-dependent cross-linking of glycoprotein (GP) II b/IIIa on activated platelets is the final mechanism leading to platel et aggregation. Inhibition of this mechanism may result in a novel ant ithrombotic agent. We studied the activity of MK-383 (L-700,462), a ne w, nonpeptide GPIIb/IIIa antagonist, in vitro and in vivo, in man. Met hods and Results. MK-383, a nonpeptide tyrosine derivative, dose-depen dently inhibited fibrinogen-dependent platelet aggregation, in vitro. Binding of I-125-labeled fibrinogen to activated platelets was prevent ed in a competitive manner with an IC50 of 10+/-4.2 nmol/L. The activi ty and tolerability of MK-383 were evaluated in a two-part double-blin d, placebo-controlled, dose-escalation study in healthy male subjects using 1- and 4-hour intravenous infusions. Effects on ADP- and collage n-induced ex vivo platelet aggregation (APA or CPA) and template bleed ing time (TBT) were evaluated. Twenty-four subjects participated in th e 1-hour part. Six received placebo and 18 MK-383 in doses ranging fro m 0.05 to 0.40 mug . kg-1 . min-1. MK-383 inhibited platelet aggregati on and prolonged bleeding time in a dose-dependent manner. APA and CPA were totally inhibited at the end of infusion of 0.4 mug . kg-1 . min -1 and returned to 55% and 89% of baseline, respectively, at 3 hours a fter infusion. TBT was prolonged at this dose from 5.0+/-1.3 minutes p redose 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 mug . kg-1 . min-1), and five rec eived placebo. Complete inhibition of ex vivo platelet aggregation was seen at 0.15 and 0.2 mug . kg-1 . min-1. At 0.2 mug . kg-1 . min-1, T BT was prolonged from 4.4+/-1.2 to 23.9+/-4.3 minutes at the end of in fusion (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 i ndicate 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 inv estigate the antithrombotic potential of this new class of antiplatele t agents.