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GPIIb/IIIa Antagonist (gpiib/iiia + antagonist)

Distribution by Scientific Domains
Medical Sciences80%

Selected Abstracts

UR-3216: A Manageable Oral GPIIb/IIIa Antagonist

CARDIOVASCULAR THERAPEUTICS, Issue 1 2001
Kosuke Baba
ABSTRACT UR-3216, a prodrug, is a novel, selective, and orally active platelet surface glycoprotein GPIIb/IIIa) receptor antagonist. The most important property of UR-3216 is the very tight binding of its active metabolite to platelets (Ki for resting platelets is <1 nM). UR-2992, the active form of UR-3216, binds to platelets for a long period of time, while the unbound drug is rapidly cleared. Therefore, after an initial loading dose of 0.1 mg/kg, only once daily repeated low maintenance doses of UR-3216 (<0.05 mg/kg p.o.) are required. This regimen maintains a high level of inhibition of platelet aggregation and, due to a small peak-to-trough ratio, severe bleeding is avoided. The therapy with UR-3216 is easy to manage, because it has low peak-to-trough ratio and high efficacy (>80% inhibition of platelet aggregation). In addition, UR-3216 does not produce excessive bleeding or thrombocytopenia and does not interact with abciximab. UR-3216 is excreted mostly in bile, so that it will not accumulate in patients with chronic renal dysfunction. UR-2316 has the following abciximab-like features: (a) its half-lives for residence on platelets, inhibition of platelets aggregation and bleeding time prolongation are 60 to 80 h, 24, and 2 h, respectively; (b) its receptor binding occupancy is similar to that of abciximab (Mab1 is inhibited and Mab2 is unaltered). In conclusion, UR-3216 is a promising, orally active GPIIb/IIIa antagonist for the treatment of cardiovascular diseases. [source]

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

DRUG DEVELOPMENT RESEARCH, Issue 3 2002
Ken-ichi Suzuki
Abstract 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-(N2 -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. Res. 55:149,161, 2002. © 2002 Wiley-Liss, Inc. [source]

A Val193Met mutation in GPIIIa results in a GPIIb/IIIa receptor with a constitutively high affinity for a small ligand

BRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2001
John Fullard
We have identified a patient designated as (GTa) with Glanzmann's Thrombasthenia (GT) diagnosed on the basis of a prolonged bleeding time and failure of the patient's platelets to aggregate. The number of glycoprotein (GP)IIb/IIIa receptors on the platelet surface was 37% of normal and those receptors displayed a defect in soluble fibrinogen binding. Nevertheless, GTa platelets showed increased adhesion to solid-phase fibrinogen and binding affinity for the RGD-mimetic 3H-SC52012, a non-peptide GPIIb/IIIa antagonist. Dithiothreitol (DTT) and ADP enhanced the affinity for [3H]-SC52012 in normal platelets, but had little effect in GTa platelets. These findings suggested that GTa platelets were locked in an altered affinity state. Genetic analysis showed that GTa was a compound heterozygote for the GPIIIa gene. One allele showed a deletion at the 3, end of exon 3 resulting in a premature stop codon. The second GPIIIa allele had a G to A transition at nucleotide 577, resulting in a Val193Met substitution. HEK 293T cells transfected with mutant GPIIb/IIIaV193M bound [3H]-SC52012 with a higher affinity than wild-type GPIIb/IIIa, and this was not increased by DTT. The mutant receptor distinguishes between platelet adhesion and aggregation, and demonstrates the phenotype that may be expected when platelet aggregation alone is inhibited. [source]

UR-3216: A Manageable Oral GPIIb/IIIa Antagonist

CARDIOVASCULAR THERAPEUTICS, Issue 1 2001
Kosuke Baba
ABSTRACT UR-3216, a prodrug, is a novel, selective, and orally active platelet surface glycoprotein GPIIb/IIIa) receptor antagonist. The most important property of UR-3216 is the very tight binding of its active metabolite to platelets (Ki for resting platelets is <1 nM). UR-2992, the active form of UR-3216, binds to platelets for a long period of time, while the unbound drug is rapidly cleared. Therefore, after an initial loading dose of 0.1 mg/kg, only once daily repeated low maintenance doses of UR-3216 (<0.05 mg/kg p.o.) are required. This regimen maintains a high level of inhibition of platelet aggregation and, due to a small peak-to-trough ratio, severe bleeding is avoided. The therapy with UR-3216 is easy to manage, because it has low peak-to-trough ratio and high efficacy (>80% inhibition of platelet aggregation). In addition, UR-3216 does not produce excessive bleeding or thrombocytopenia and does not interact with abciximab. UR-3216 is excreted mostly in bile, so that it will not accumulate in patients with chronic renal dysfunction. UR-2316 has the following abciximab-like features: (a) its half-lives for residence on platelets, inhibition of platelets aggregation and bleeding time prolongation are 60 to 80 h, 24, and 2 h, respectively; (b) its receptor binding occupancy is similar to that of abciximab (Mab1 is inhibited and Mab2 is unaltered). In conclusion, UR-3216 is a promising, orally active GPIIb/IIIa antagonist for the treatment of cardiovascular diseases. [source]

Orbofiban: An orally active GPIIb/IIIa platelet receptor antagonist

MEDICINAL RESEARCH REVIEWS, Issue 3 2001
Nancy S. Nicholson
Abstract 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 t1/2 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. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 3, 211,226, 2001 [source]