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

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 (IC50 = 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. Res. 61:233–241, 2004.