SC-54684A: An Orally Active Inhibitor of Platelet Aggregation

Nicholson, Nancy S.; Panzer‐Knodle, Susan G.; Salyers, Anita K.; Taite, Beatrice B.; Szalony, James A.; Haas, Neal F.; King, Lucy W.; Zablocki, Jeffery A.; Keller, Bradley T.; Broschat, Kay O.; Engleman, V. Wayne; Hérin, Michel; Jacqmin, P.; Feigen, Larry P.

doi:10.1161/01.cir.91.2.403

Cited by 55 publications

(31 citation statements)

References 26 publications

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“…The active moiety of xemilofiban is a potent, specific inhibitor of fibrinogen binding that blocks platelet aggregation to all known stimuli. 3 A previous study demonstrated that administration of xemilofiban to conscious dogs resulted in dose-dependent antiplatelet activity and a high level of bioavailability. 10 In this report, we assessed for the first time the antithrombotic effectiveness of orally administered xemilofiban or xemilofiban with ASA in a canine model of coronary artery thrombosis.…”

Section: Discussionmentioning

confidence: 99%

“…The hydrochloride salt (SC-54701A) of the active moiety of xemilofiban is a potent inhibitor of fibrinogen binding to platelets. 3 This compound is highly selective for the GP IIb/IIIa receptor compared with other integrins sharing the same ␤ 3 -subunit. 3 ASA is the most convenient and widely tested antiplatelet agent, but this drug possesses limited antithrombotic efficacy.…”

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confidence: 99%

“…3 This compound is highly selective for the GP IIb/IIIa receptor compared with other integrins sharing the same ␤ 3 -subunit. 3 ASA is the most convenient and widely tested antiplatelet agent, but this drug possesses limited antithrombotic efficacy. Clinical studies show that the incidence of acute myocardial infarction is reduced 40% by ASA, 4 yet the event may occur during ASA therapy in 1% of individuals free of prior myocardial infarction, 5 in 4% of patients with unstable angina, 6 and in 24% of patients with prior myocardial infarction.…”

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confidence: 99%

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Protective Effect of Oral Xemilofiban in Arterial Thrombosis in Dogs

Frederick¹,

Suleymanov²,

Szalony³

et al. 1998

Circulation

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Background-Inhibition of platelet aggregation by preventing the binding of fibrinogen to glycoprotein (GP) IIb/IIIa on activated platelets results in antithrombotic activity. We report on the antithrombotic effect of xemilofiban (SC-54684A), an oral GP IIb/IIIa antagonist, administered alone or with aspirin (ASA) in an acute thrombosis model. Methods and Results-Conscious dogs were treated with xemilofiban (1.25, 2.5, 5.0, or 6 mg/kg, nϭ6); low-dose (LD, 81 mg) ASA, nϭ7; high-dose (HD, 162 mg) ASA, nϭ6; xemilofibran 1.25 mg/kg plus LD ASA, nϭ6; xemilofibran 1.25 mg/kg plus HD ASA, nϭ6; or placebo, nϭ7. Dogs were anesthetized 60 minutes later, and the effects of the treatments were evaluated after electrolytic injury (250 A for 180 minutes) in the left circumflex coronary artery. Bleeding time (BT) was assessed in a separate study. Incidence of thrombosis was reduced (PϽ0.05) by xemilofiban Ն2.5 mg/kg, HD ASA, or xemilofiban 1.25 mg/kg plus HD ASA compared with placebo. Xemilofiban Ն2.5 mg/kg or xemilofiban 1.25 mg/kg plus HD ASA significantly increased time to occlusion, inhibited ex vivo platelet aggregation to collagen Ͼ90%, and prevented or decreased (PϽ0.05) cyclic flow variations (CFVs) compared with placebo. BT was increased (PϽ0.05) with xemilofiban Ն2.5 mg/kg but not with xemilofiban 1.25 mg/kg plus HD ASA. Conclusions-Xemilofiban Ն2.5 mg/kg, HD ASA, or xemilofiban 1.25 mg/kg plus HD ASA significantly reduced the incidence of thrombosis. These doses of xemilofiban or xemilofiban 1.25 mg/kg plus HD ASA increased time to occlusion, inhibited ex vivo platelet aggregation by Ͼ90%, and prevented or reduced CFVs. Xemilofiban Ն2.5 mg/kg but not xemilofiban 1.25 mg/kg plus HD ASA significantly increased BT. (Circulation. 1998;98:813-820.)

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Protective Effect of Oral Xemilofiban in Arterial Thrombosis in Dogs

Frederick¹,

Suleymanov²,

Szalony³

et al. 1998

Circulation

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“…Nicholson et al [1995] reported that the bioavailability of SC-54684A in dogs was 21.3%. Furthermore, YM128 showed good availability (22.2%) in cynomolgus monkeys also.…”

Section: Oral Route Ym128mentioning

confidence: 99%

Pharmacodynamics and pharmacokinetics of YM128, a GPIIb/IIIa antagonist prodrug

Suzuki¹,

Moritani²,

Hisamichi³

et al. 2002

Drug Development Research

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We examined the biochemical properties of YM-57029 ({4-[4-(4-Carbamimidoylphenyl)-3-oxopiperazin-1-yl]piperidino}acetic acid monohydrochloride trihydrate) and the pharmacodynamics and pharmacokinetics of its prodrug, YM128 (Ethyl (Z)-(4-{4-[4-(N 2 -hydroxycarbamimidoyl)phenyl]-3-oxopiperazin-1-yl}piperidino)acetate), an orally-active glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist. YM-57029 strongly inhibited aggregation of human platelets induced by various agonists, with IC50 values ranging from 3.6 to 51 nM. YM-57029 specifically inhibited fibrinogen binding to purified GPIIb/IIIa about 1,000-fold more potently than Arg-Gly-Asp-Ser (RGDS). Moreover, YM-57029 effectively inhibited an Arg-Gly-Asp (RGD) peptide binding to platelets, suggesting that YM-57029 competed with the RGD sequence of ligand. YM-57029 or YM128 dose-dependently inhibited ex vivo platelet aggregation after iv bolus injection or oral administration to beagle dogs and cynomolgus monkeys. However, YM128 exerted more potent and prolonged inhibitory effects on platelet aggregation than YM-57029 after oral administration to cynomolgus monkeys. Furthermore, YM-57029 prolonged template bleeding time at a dose that inhibited ex vivo platelet aggregation during cumulative iv infusion to cynomolgus monkeys. Metabolic and pharmacokinetic studies showed that YM128 effectively converted into YM-57029 in liver microsomes from humans as well as dogs and monkeys, and that bioavailabilities of YM128 in dogs and monkeys were 32.3 and 22.2%, respectively. These results suggest that YM128, a prodrug of YM-57029, may be a valuable GPIIb/IIIa antagonist with good bioavailability in humans. Drug Dev.

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“…This compared very favorably with the oral systemic availability of other oral GP IIb/IIIa inhibitors that entered development, which ranged from 9 to 25%. 32,54,55 Another favorable pharmacokinetic parameter that made orbo®ban attractive for long-term use was its relatively long half-life of 18 hr in dogs, which made a twice-daily dosing regimen feasible. …”

Section: P R E C L I N I C a L P H A R M A C O L O G Ymentioning

confidence: 99%

Orbofiban: An orally active GPIIb/IIIa platelet receptor antagonist

Nicholson¹,

Abood²,

Panzer‐Knodle³

et al. 2001

Medicinal Research Reviews

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A key role has been established for platelet activation and thrombus formation in the pathogenesis of acute coronary syndromes, and restenosis after percutaneous interventions. Antiplatelet agents that have a wider spectrum of activity than aspirin, and clopidogrel would be expected to provide improved antithrombotic protection. Preclinical studies were used to predict clinical efficacy of orally active GPIIb/IIIa antagonists such as xemilofiban, sibrafiban, lefradafiban, and orbofiban. While clinical trials have shown potent and sustained platelet inhibition, outcomes of trials with these first generation GPIIb/IIIa compounds have been disappointing. The active moiety of orbofiban is a potent and specific inhibitor of fibrinogen binding to GPIIb/IIIa, leading to inhibition of platelet aggregation to a wide variety of agonists. Studies comparing inhibition of aggregation and bleeding suggest that chronic inhibition of platelet aggregation can be achieved without major bleeding side effects. Thrombus formation is prevented in canine models of thrombosis. Orbofiban is approximately 28% bioavailable with a t(1/2) of 18 hr. The high bioavailability, long half-life, and potential safety suggest orbofiban would be suitable for chronic oral administration. Clinical data demonstrate that orally administered orbofiban has the desired pharmacodynamic effect of inhibiting platelet aggregation but does not demonstrate clinical benefit when examined in large-scale trials.

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SC-54684A: An Orally Active Inhibitor of Platelet Aggregation

Abstract: SC-54684A, an orally active antiplatelet drug now in clinical trial, is shown to be a potent, specific fibrinogen binding inhibitor that blocks platelet aggregation to a wide variety of known stimuli and has good bioavailability in animals.

Cited by 55 publications

References 26 publications

Protective Effect of Oral Xemilofiban in Arterial Thrombosis in Dogs

Protective Effect of Oral Xemilofiban in Arterial Thrombosis in Dogs

Pharmacodynamics and pharmacokinetics of YM128, a GPIIb/IIIa antagonist prodrug

Orbofiban: An orally active GPIIb/IIIa platelet receptor antagonist

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