Human in vitro pharmacodynamic profile of the selective Factor Xa inhibitor ZK-807834 (CI-1031)

Post, Joseph; Sullivan, M.; Abendschein, Dana R.; Ewing, Janice; Hinchman, Josephine W; Light, David R.

doi:10.1016/s0049-3848(02)00024-5

Cited by 7 publications

(3 citation statements)

References 18 publications

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“…The methods of botha ssays have be describedi nd etaili no ur previous publication (19).B riefly, the prothrombin time (PT), activatedpartialthromboplastin time(aPTT)and thrombin clot time(TT) were measured using reagentsfrom Sigma and aprogrammablec oagulometer( MLA Electra 1400C).L yophilized human plasma (S.A.R.P. ; Helena Laboratories) or fresh rabbit plasma were spiked with BX 528 (0.01 -3 00 µg/ml).…”

Section: In-vitro Coagulation and Platelet Aggregation Assaysmentioning

confidence: 99%

A novel inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) – Part I: Pharmacological characterization

Wang¹,

Zhao²,

Nagashima³

et al. 2007

Thromb Haemost

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SummaryWe have discovered a novel small-molecule (3-phosphinoylpropionic acid) inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa), BX 528, which had an IC50 of 2 nM in an enzymatic assay and 50 nM in an in-vitro clot lysis assay, with 3,500- to 35,000-fold selectivity against other carboxypeptidases, such as CPN, CPZ and CPD, and 5- and 12-fold selectivity against CPE (CPH) and CPB, respectively. At 10 µM, BX 528 had no significant activity (< 50% inhibition or antagonism) in a panel of 137 enzymes and receptors. It had no effects on blood coagulation and platelet aggregation up to 300 and 10 µM, respectively. The plasma half-life following intravenous administration was 0.85 hours in rats and 4.5 hours in dogs. No significant metabolism was detected in human, dog or rabbit hepatic microsomes, and no significant inhibition of cytochrome P450 3A4 and 2D6 up to 30 µM. No cytotoxic or cell proliferative effects were found in three hepatic and renal cell lines up to 300 µM and no mutagenic activity was seen in the Ames II screen. There were no significant hemodynamic effects in rats and dogs up to 100 and 30 mg/kg with peak plasma drug concentrations of ~1,000 and 300 µM, respectively. In an in-vivo complement activation model in guinea pigs, BX 528 showed minimal inhibition of plasma CPN activity up to 60 mg/kg with peak plasma concentrations up to 250 µM. Thus, these data demonstrate that BX 528 is a novel, potent, selective and safe TAFIa inhibitor.

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Section: In-vitro Coagulation and Platelet Aggregation Assaysmentioning

confidence: 99%

A novel inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) – Part I: Pharmacological characterization

Wang¹,

Zhao²,

Nagashima³

et al. 2007

Thromb Haemost

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“…When ZK-807834 was tested in a veno-venous shunt model of thrombosis in rabbits, it exhibited a promising efficacy-to-bleeding ratio [43]. The human in vitro pharmacodynamic analysis appears to be favourable [44] and as of 2002, ZK-807834 was planned to enter clinical testing.…”

Section: Direct Factor Xa Inhibitorsmentioning

confidence: 99%

New antithrombotic drugs on the horizon

Ruef¹,

Katus²

2003

Expert Opinion on Investigational Drugs

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Venous and arterial thromboembolism are a major cause for morbidity and mortality. The list of established drugs for the prevention of thrombus formation and embolisation includes heparins, hirudin and derivatives, aspirin, ADP and glycoprotein IIb/IIIa receptor antagonists, as well as vitamin K antagonists. Several limitations exist for these drugs that have stimulated the search for new and better anticoagulants. A series of selective clotting factor Xa inhibitors and direct factor IIa (thrombin) inhibitors are on the horizon, two of which are getting close to broad clinical application. Additional therapeutics that are still under preclinical and clinical investigation include inhibitors of the tissue factor pathway/factor VII complex, clotting factor VIII and XIII inhibitors and modulators of the protein C pathway or of endogenous fibrinolysis, as well as novel antiplatelet drugs. This review is focused on the current status of development of novel antithrombotics and their clinical potential. Even though only a few of a broad array of antithrombotic agents have reached clinical testing, some hold the potential for significant improvement in efficacy and safety of anticoagulant therapy.

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“…Direct factor-Xa inhibitors have establishedantithrombotic efficacyinmodel systems and have promising hemostatic safety profiles (20)(21)(22). Factor-Xa inhibition is potent, highly selective,safe and moreefficaciousthan standard heparin and low-molecular-weight heparininanimal models (6,(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients

Zafar¹,

Farkouh²,

Osende³

et al. 2007

Thromb Haemost

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It was the objective of this study to evaluate the anti-thrombotic potency of direct factor-Xa inhibition with ZK-807834 in stable coronary patients, using an ex-vivo model of arterial thrombus formation. Tissue factor pathway is important in atherothrombosis. Direct factor-Xa blockade may more potently reduce thrombosis and prevent coronary events. Badimon Perfusion Chamber 5-minute quantitative studies have shown 40-55% arterial thrombus reduction with abciximab, 23% with clopidogrel, but none with heparin. Coronary patients (n = 18, 59 +/- 9 years, 55% males) were blindly randomized to four groups receiving 24-hour infusion of a low, medium or high dose of direct factor- Xa inhibitor ZK-807834, or placebo. Arterial thrombus formation was measured in Badimon Chamber at baseline, end-of-infusion [EoI], and four hours and eight hours after EoI, and factor-X activity, prothrombin time [PT] ratio and plasma drug levels were measured simultaneously. For the low-, medium- and high-dose ZK-807834 groups, mean percent-reduction in thrombus size from baseline to EoI were 29%, 34% and 68%, respectively (p < 0.001), and at 8-h post EoI were 11%, 19% and 27%, respectively (p < 0.01). Mean PT-ratio prolongation showed a strong linear relationship (Pearson's r = 0.93) with ZK-807834 plasma concentration. Mean percent-reduction in factor-X activity from baseline was 13%, 42% and 58%, respectively. Placebo had no effect on thrombus size or factor-X activity. In conclusion, direct factor-Xa inhibition with ZK-807834 markedly reduces ex-vivo arterial thrombus formation and factor-X activity in a dose-dependent manner. Plasma levels of ZK-807834 show a strong linear correlation with PT ratio. This direct factor-Xa inhibitor may reduce the need for additional potent glycoprotein IIbIIIa inhibition.

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Human in vitro pharmacodynamic profile of the selective Factor Xa inhibitor ZK-807834 (CI-1031)

Cited by 7 publications

References 18 publications

A novel inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) – Part I: Pharmacological characterization

A novel inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) – Part I: Pharmacological characterization

New antithrombotic drugs on the horizon

Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients

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