» Articles » PMID: 9732389

Antiplatelet Efficacy of XV459, a Novel Nonpeptide Platelet GPIIb/IIIa Antagonist: Comparative Platelet Binding Profiles with C7E3

Overview
Specialty Pharmacology
Date 1998 Sep 11
PMID 9732389
Citations 4
Authors
Affiliations
Soon will be listed here.
Abstract

Recent advances in the development of i.v. platelet glycoprotein alphaIIb/beta3 integrin (GPIIb/IIIa) antagonists led to the development of either a class of small-molecular-weight antagonists with a short to ultra-short duration of antiplatelet effects (Integrelin, Tirofiban, DMP728) or a very long-acting antagonist (ReoPro). Thus the present study was undertaken to characterize the antiplatelet efficacy of a small-molecule GPIIb/IIIa antagonist, DMP754/XV459, and to determine its platelet GPIIb/IIIa receptor binding profiles. DMP754, upon its conversion with esterases to its free acid form XV459, and XV459 itself, demonstrated high potency (IC50 = 0.030-0.060 microM) in inhibiting human platelet aggregation induced by ADP (100 microM), thrombin receptor agonist peptide (10 microM) or collagen (20 microgram/ml) in citrate or heparin. Maximal platelet aggregation inhibition was achieved at 50 to >/=80% receptor occupancy, depending on the agonist used. Both XV459 and c7E3 bind with high affinity to either activated human platelets (Kd = 0.0008 and 0.0091 microM, respectively) or unactivated human platelets (Kd = 0.0025 and 0.0092 microM, respectively). XV459 demonstrated tight association with human, baboon and (to a lesser extent) canine platelets (t1/2 of dissociation = 7 +/- 0, 8 +/- 1 and 1.4 +/- 0.1 minutes, respectively). Both c7E3 and XV459 associate tightly with slower dissociation rates to unactivated human platelets. XV459 represents a potent antiplatelet agent in inhibiting platelet aggregation along with offering high affinity and a relatively slow dissociation rate from human platelet GPIIb/IIIa receptors that might allow for once-a-day p.o. dosage.

Citing Articles

Platelet integrin αIIbβ3 plays a key role in a venous thrombogenesis mouse model.

Adair B, Field C, Alonso J, Xiong J, Deng S, Ahn H Nat Commun. 2024; 15(1):8612.

PMID: 39366965 PMC: 11452527. DOI: 10.1038/s41467-024-52869-3.


Exogenous Integrin αIIbβ3 Inhibitors Revisited: Past, Present and Future Applications.

van den Kerkhof D, van der Meijden P, Hackeng T, Dijkgraaf I Int J Mol Sci. 2021; 22(7).

PMID: 33806083 PMC: 8036306. DOI: 10.3390/ijms22073366.


Oral platelet glycoprotein IIb/IIIa receptor inhibitors--part II.

Cannon C Clin Cardiol. 2003; 26(9):401-6.

PMID: 14524594 PMC: 6654522. DOI: 10.1002/clc.4960260903.


Platelet GPIIb/IIIa binding characteristics of small molecule RGD mimetic: distinct binding profile for Roxifiban.

Mousa S, Bozarth J, Naik U, Slee A Br J Pharmacol. 2001; 133(3):331-6.

PMID: 11375248 PMC: 1572788. DOI: 10.1038/sj.bjp.0703943.