XV454, a novel nonpeptide small-molecule platelet GIIb/IIIa antagonist with comparable platelet alpha(IIb)beta3-binding kinetics to c7E3
| Autor: | Mark S. Forsythe, Jeffrey M. Bozarth, Ashraf F Youssef, Thais M. Sielecki, John Wityak, Shaker A. Mousa, Rick E. Olson |
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| Rok vydání: | 1998 |
| Předmět: |
Blood Platelets
Male Integrins Platelet Aggregation Swine Enzyme-Linked Immunosorbent Assay Platelet Glycoprotein GPIIb-IIIa Complex Pharmacology chemistry.chemical_compound Dogs Thrombin receptor Potency Animals Humans Platelet Vitronectin Receptor IC50 Oxazoles Alanine Chemistry Antagonist Antibodies Monoclonal Receptor–ligand kinetics Adenosine diphosphate Kinetics Biochemistry Female Cardiology and Cardiovascular Medicine Platelet Aggregation Inhibitors Papio |
| Zdroj: | Journal of cardiovascular pharmacology. 32(5) |
| ISSN: | 0160-2446 |
| Popis: | XV454 demonstrated high potency (IC50 = 14-25 nM) in inhibiting human platelet aggregation induced by adenosine diphosphate (ADP, 10 microM), thrombin receptor agonist peptide (TRAP) (10 microM), or collagen (20 microg/ml). XV454 exhibited a high degree of selectivity for platelet alpha(IIb)beta3 in comparison with c7E3, which is a nonspecific antagonist for both alpha(IIb)beta3 and alpha(v)beta3. Both XV454 and c7E3 bind with high affinity to either activated (A) or unactivated (U) human, baboon, or canine platelets. XV454 binds with a relatively higher affinity [Kd = 0.5 nM (A), 0.6 nM (U)] as compared with c7E3 [Kd = 9.1 nM (A), 9.2 (U) nM]. XV454 demonstrated a tight association with human, baboon, and, to a lesser extent, with canine platelets (t(1/2) of dissociation = 110 +/- 6, 80 +/- 10, and 23 +/- 2 min, respectively). Both c7E3 and XV454 associate tightly with a slower dissociation rate with unactivated human platelets: t(1/2) of 42 and 116 min, respectively. In non-human primates, oral (0.1 mg/kg, p.o.) and intravenous (0.05 mg/kg, i.v. bolus administration of XV454 methyl ester pro-drug resulted a long-lasting maximal antiplatelet efficacy for < or = 72 h with significant but reversible prolongation of bleeding time and without effects on platelet count, clinical chemistry, or hemodynamic profile. In conclusion, XV454 represents a potent antiplatelet agent in inhibiting platelet aggregation along with a high affinity and relatively slow dissociation rate from human platelet GPIIb/IIIa receptors that allow a long-lasting antiplatelet efficacy after single i.v. or oral administration. |
| Databáze: | OpenAIRE |
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