Characterization of the anti‐platelet actions of FK419, a novel non‐peptide antagonist of platelet GPIIb/IIIa

Abstract

The anti-platelet properties of FK419 ((S)-2-acetylamino-3-[(R)- [1-[3-(piperidin-4-yl)propionyl]piperidin-3-ylcarbonyl] amino]propionic acid), a novel non-peptide GPIIb/IIIa antagonist, were compared in a variety of experimental settings, both in vitro and in vivo, with other GPIIb/IIIa antagonists including xemilofiban, lamifiban, tirofiban, and FK633. Receptor binding studies suggested that FK419 had potent GPIIb/IIIa antagonistic activity that is comparable with those of reference antagonists. FK419 effectively inhibited human platelet aggregation, regardless of agonist stimuli (IC 50 ¼ 35-170 nM). FK419 demonstrated in vitro species-dependent anti-platelet activity, with higher potency in human than in dog, guinea pig, or rat tissue, and dose-dependently inhibited ex vivo platelet aggregation in dogs and guinea pigs. In contrast to other antagonists, FK419 minimally affected template bleeding time at doses that completely inhibited platelet aggregation in canines. These results demonstrate that FK419 is a novel, potent, and selective GPIIb/IIIa antagonist that safely inhibits platelet aggregation in vivo, suggesting that it may be a promising anti-platelet agent for thrombotic diseases. Drug Dev.

FK419, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, Ameliorates Brain Infarction Associated with Thrombotic Focal Cerebral Ischemia in Monkeys: Comparison with Tissue Plasminogen Activator

“…We recently reported that FK419 dose-dependently prevented the reocclusion of MCA after recanalization in photothrombotic MCA occlusion model in guinea-pigs (Moriguchi et al , 2004 a ). FK419 was found not only to prevent reocclusion but also to thrombolyse the obstructive thrombus in a similar model (Moriguchi et al , 2004 b ; Moriguchi et al , 2005). However, the clinical predictive value of this model is limited because numerous compounds that were active in rodent models have failed in clinical trials.…”

“…Recently, abciximab, an antibody directed to GPIIb/IIIa receptor, was found to have beneficial effects in acute ischemic stroke (AbESTT Investigators, 2003). FK419 ((S)-2-acetylamino-3-[(R)-[1-3-(piperidin-4-yl)propionyl]piperidin-3-ylcarbonyl]amino]propionic acid trihydrate) is a novel nonpeptide GPIIb/IIIa receptor antagonist with strong antiplatelet efficacy (Mihara et al , 2004). Furthermore, it has been demonstrated that FK419 effectively dispersed aggregating platelets and improved neurologic deficits and reduced brain damage in guinea-pig thrombotic middle cerebral artery (MCA) occlusion model (Moriguchi et al , 2004 b ).…”

Association of the antagonism of von Willebrand factor but not fibrinogen by platelet αIIbβ3 antagonists with prolongation of bleeding time

“…FK419 [15], FK633 [16], FR184764, FR233229, FR231643, lamifiban [17], xemilofiban [18], and tirofiban [19] (Fig. 1) were synthesized in Fujisawa Pharmaceutical Co., Ltd (Osaka, Japan), with purity >98% by HPLC and mass spectrum analysis.…”

FK419, a Novel Nonpeptide GPIIb/IIIa Antagonist, Restores Microvascular Patency and Improves Outcome in the Guinea-Pig Middle Cerebral Artery Thrombotic Occlusion Model: Comparison with Tirofiban

“…GPIIb/IIIa antagonists are expected to be effective in these phenomena, and abciximab, a monoclonal anitibody, and tirofiban, a nonpeptide antagonist, have been clinically evaluated for their efficacy in acute stroke patients (Junghans et al , 2002; AbESTT Investigators, 2003; Seitz et al , 2003; Straub et al , 2004). We have recently identified FK419 (( S )-2-acetylamino-3-[( R )-[1-[3-(piperidin-4-yl) propionyl]piperidin-3-ylcarbonyl]amino]propionic acid trihydrate) as a novel nonpeptide GPIIb/IIIa antagonist with high affinity for the GPIIb/IIIa complex (Mihara et al , 2004). Selective ligand inhibition by FK419 enabled almost complete inhibition of platelet aggregation without prolongation of bleeding time in dogs (Aoki et al , unpublished observation).…”