Jeffery A. Zablocki*, Shashidhar N. Rao, David A. Barone, Daniel L. Flynna, Nancy S. Nicholson and Larry P. Feigen Pages 533 - 558 ( 26 )
Fibrinogen receptor antagonists represent a potential new form of antithrombotic therapy for the treatment or prevention of vascular complications [ie. myocardial infarct (MI)]. They function by disrupting the fibrinogen-platelet glycoprotein lib-Illa (GP Ilb-IIla) interaction and inhibit platelet aggregation induced by all platelet activating agents. By contrast, aspirin (ASA), one current form of therapy, blocks only one path of platelet activation (tbromboxane Az). c7E3, a fibrinogen receptor antagonist antibody, has recently been approved for use in high risk PTCA patients. A 35% reduction in Mls and repeat angioplasty with c7E3 treatment (bolus plus infusion) was observed compared to a 20% reduction with ASA treatment at the six month point. After promising Phase II studies with Integrelin, Phase ID studies (IMPACT) in PTCA at altered doses did not show statistically significant differences relative to placebo, suggest that a critical issue with fibrinogen receptor antagonists is careful selection of an efficacious dose balanced against overdosing with potential of increased bleeding events. Three additional IV agents (MK-383, 18; BIBU-52, 41; Ro 44-9883, 55) show promising results in Phase II trials for unstable angina and high risk PTCA. Orally active fibrinogen receptor antagonists, designed for chronic administration, are entering clinical trials to prevent a secondary MI or to treat unstable angina. In Phase I studies with SC-54684A 4A, a single 50 mg oral dose inhibited ADP platelet aggregation for up to 10 hours. In another Phase I study, BIBU 104 (a bis-prodrug of BIBU 52), an oral dose (25-150 mg) led to dose proportional inhibition of aggregation. Other fibrinogen receptor antagonists demonstrating oral activity in animal models, are at different stages of preclinical development (21, 31, 39, 49, 53-analog, 548, 57, 59). The approach and evolution of design of four series of fibrinogen receptor antagonists is described in detail. Potential binding modes of inhibitors and receptor-ligand interactions are discussed including a discussion of the y-chain dodecapeptide and RGD receptor binding sites. The disruption of signal transduction pathways of the GP IIb-IIIa receptor involving inside-out and outside-in signaling are briefly described as relevant to a series of inhibitors (67 and 68). The similarity of the RGD and dodecapeptide binding motifs coupled with mutiple receptor binding sites, outside-in signal transduction, and potential differential inhibition of storage granule release reactions suggest that not all fibrinogen receptor antagonists are platelet physiologically equivalent based on similar levels of platelet inhibition. Although the nature of antagonism may differ, it is not obvious that clinical differences will be observed. The critical issues with fibrinogen receptor antagonists are still the steepness of the dose response curve, the ability to select doses that provide efficacy without an overt increase in bleeding risk, and rapid reversal of therapy if complications arise.