Orally Active Isoxazoline GPIIb/IIIa Antagonists

Mousa, Shaker A.; Wityak, John

doi:10.1111/j.1527-3466.1998.tb00344.x

Cited by 31 publications

(19 citation statements)

References 46 publications

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“…In some PRP samples from the vehicle group, DMP802 at 3 lM was spiked in the vehicle-treated PRP. DMP802 is a GPIIb/IIIa receptor antagonist and was included as a positive control (IC 50 = 29 nM against human platelet aggregation response to 10 lM ADP) [33].…”

Section: Platelet Aggregation Assaysmentioning

confidence: 99%

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

Wong

Crain

Watson

et al. 2011

J Thromb Thrombolysis

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BMS-262084 is a 4-carboxy-2-azetidinone-containing irreversible inhibitor of FXIa, which is selective over other coagulation proteases. We evaluated the in vitro and in vivo properties of BMS-262084 in rabbits. Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrolytic-mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. BMS-262084 was infused IV from 1 h before thrombus induction or cuticle transection to the end of the experiment. In vitro, BMS-262084 prolonged activated partial thromboplastin time (aPTT) with EC(2x) (concentration required to double aPTT) of 10.6 μM in rabbit plasma, and did not prolong prothrombin time (PT), thrombin time (TT) and HepTest. In vivo, BMS-262084 produced dose-dependent antithrombotic effects in rabbits with antithrombotic ED(50) (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT of 0.4, 0.7 and 1.5 mg/kg/h IV, respectively. BMS-262084 increased ex vivo aPTT dose-dependently without changes in PT and TT. The antithrombotic effect of BMS-262084 was significantly correlated with its ex vivo aPTT, supporting the use of ex vivo aPTT as a pharmacodynamic biomarker. BMS-262084 did not alter ex vivo rabbit platelet aggregation to ADP and collagen. BT (fold-increase) determined at 3 and 10 mg/kg/h of BMS-262084 were 1.17 ± 0.04 and 1.52 ± 0.07*, respectively (*P < 0.05 vs. control). This study demonstrated that BMS-262084 prevented experimental thrombosis at doses with low BT effects in rabbits, and suggests that a small molecule FXIa inhibitor may represent a promising antithrombotic therapy.

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Section: Platelet Aggregation Assaysmentioning

confidence: 99%

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

Wong

Crain

Watson

et al. 2011

J Thromb Thrombolysis

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“…Clinical studies with orally active GPIIb/IIIa antagonists (including xemilofiban, orbofiban, sibrafiban, lotrafiban, and lefradafiban) demonstrated oral antiplatelet activity (ex-vivo inhibition of platelet aggregation) in humans [25][26][27][28][29], although the development programs for xemilofiban, orbofiban, sibrafiban, and lotrafiban were discontinued because of lack of clinical benefit [30][31][32]. The roxifiban active form XV459 has distinct platelet Platelet GPIIb/IIIa antagonist and r-tPA Mousa 57 Data represent the mean AE SEM, n ¼ 5.…”

Section: Discussionmentioning

confidence: 99%

“…Data represent the mean AE SEM, n ¼ 6. GPIIb/IIIa binding characteristics, regardless of the platelet agonist or the anticoagulant used (citrate versus heparin), which was also discontinued in the face of the failure of the earlier antagonists and the complexity of the trials [14,[30][31][32]. Class I antagonists such as the roxifiban active form XV459 inhibited in-vitro platelet/ fibrin-mediated clot strength, with an IC 50 value of 74 nmol/l, whereas the IC 50 value of the Class II antagonists such as orbofiban, sibrafiban, integrilin, or aggrastat ranged from 1 to 15 mmol/l, which is 10-fold to 15-fold greater than their clinically achievable levels.…”

Section: Discussionmentioning

confidence: 99%

In-vitro efficacy of different platelet glycoprotein IIb/IIIa antagonists and thrombolytics on platelet/fibrin-mediated clot dynamics in human whole blood using thrombelastography

Mousa¹

2007

Blood Coagulation &Amp; Fibrinolysis

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Suppressing platelet activation improves efficacy of thrombolytic therapy for stroke and acute myocardial infarction. Combination treatment with recombinant tissue plasminogen activator (r-tPA) and glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor that binds with high affinity to platelets may therefore improve the efficacy of thrombolytic therapy. The effect of platelet GPIIb/IIIa antagonists and/or r-tPA on the dynamics of platelet/fibrin clot formation, strength, and lysis was determined using thrombelastography in human blood under thrombin or tissue factor stimulation. The study utilized platelet GPIIb/IIIa antagonists with high affinity and slow off-rate (Class I) from resting and activated platelets in comparison with Class II antagonists (lower affinity and fast off-rate from platelet GPIIb/IIIa receptors). The combination of the active form of roxifiban (XV459; Class I) or the active form of orbofiban (Class II) with a subeffective concentration of r-tPA resulted in a synergistic effect in clot lysis with roxifiban active form XV459 but not with that of orbofiban at therapeutically achievable concentrations that inhibit human platelet aggregation. These data indicate differential enhanced thrombolysis of low levels of r-tPA with high-affinity Class I but not with low-affinity Class II GPIIb/IIIa antagonists in the absence of anticoagulants.

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“…The effect on the bleeding time is reversible while maximal inhibition of platelet aggregation is maintained. 29 Roxifiban demonstrated significant antithrombotic efficacy (PϽ0.001) when administered intravenously or orally at relatively low doses in different settings or arterial thrombosis in canine. 30 After bolus administration of roxifiban in dogs, plasma concentration declined polyexponentially with a terminal halflife of 12 hours.…”

Section: L-738167mentioning

confidence: 97%

Synthetic Inhibitors of Platelet Glycoprotein IIb/IIIa in Clinical Development

Verstraete

2000

Circulation

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Activation of the platelet glycoprotein (GP IIb/IIIa) receptor on the platelet surface is the final pathway of platelet aggregation, regardless of the initiating stimulus. Inhibitors of GP IIb/IIIa receptors include monoclonal antibodies (abciximab) against this receptor and peptidic and nonpeptidic synthetic specific receptor blockers. Abciximab exchanges between and binds to platelets for as long as 2 weeks, whereas synthetic GP IIb/IIIa inhibitors inhibit ex vivo platelet aggregation for only a few hours after the end of infusion, but some have the advantage of also being orally active. In the secondary prevention of atherothrombosis, large-scale trials were successfully conducted with aspirin, dipyridamole, ticlopidine, and clopidogrel. In the first large-scale trials with GP IIb/IIIa inhibitors, abciximab was investigated. In aggregate, synthetic GP IIb/IIIa inhibitors, combined with aspirin and heparin, were shown to reduce ischemic events in patients with high- and low-risk coronary intervention, stents, unstable angina, and non-Q-wave infarction. With short-term use of synthetic GP IIb/IIIa inhibitors, there is no suppression of clinical evident restenosis 6 months after the end of treatment. With the doses currently used, bleeding occurs more often with the synthetic GP IIb/IIIa inhibitors (used for 3 days) than with abciximab (used for 12 hours), but there are no direct comparisons between these drugs.

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Orally Active Isoxazoline GPIIb/IIIa Antagonists

Cited by 31 publications

References 46 publications

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

In-vitro efficacy of different platelet glycoprotein IIb/IIIa antagonists and thrombolytics on platelet/fibrin-mediated clot dynamics in human whole blood using thrombelastography

Synthetic Inhibitors of Platelet Glycoprotein IIb/IIIa in Clinical Development

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