title: Antiplatelet efficacy of XV459, a novel nonpeptide platelet GPIIb/IIIa antagonist: comparative platelet binding profiles with c7E3.
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.
authors.affiliation: DuPont Pharmaceuticals Co., Wilmington, Delaware, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Mousa
authors.forename: J M
authors.initials: JM
authors.lastname: Bozarth
authors.forename: W
authors.initials: W
authors.lastname: Lorelli
authors.forename: M S
authors.initials: MS
authors.lastname: Forsythe
authors.forename: M J
authors.initials: MJ
authors.lastname: Thoolen
authors.forename: A M
authors.initials: AM
authors.lastname: Slee
authors.forename: T M
authors.initials: TM
authors.lastname: Reilly
authors.forename: P A
authors.initials: PA
authors.lastname: Friedman
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism*; D004285:Dogs; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000378:metabolism*; D010215:Papio; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000596:Amino Acids; D000911:Antibodies, Monoclonal; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C104284:XV 459; D005340:Fibrinogen