title: XV454, a novel nonpeptide small-molecule platelet GIIb/IIIa antagonist with comparable platelet alpha(IIb)beta3-binding kinetics to c7E3.
abstract: 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.
authors.affiliation: DuPont Pharmaceuticals Company, Wilmington, Delaware, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Mousa
authors.forename: M
authors.initials: M
authors.lastname: Forsythe
authors.forename: J
authors.initials: J
authors.lastname: Bozarth
authors.forename: A
authors.initials: A
authors.lastname: Youssef
authors.forename: J
authors.initials: J
authors.lastname: Wityak
authors.forename: R
authors.initials: R
authors.lastname: Olson
authors.forename: T
authors.initials: T
authors.lastname: Sielecki
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism*; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D010080:Oxazoles / Q000494:pharmacology*; D010215:Papio; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013552:Swine; D019096:Vitronectin / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D016023:Integrins; D010080:Oxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019096:Vitronectin; C116340:XV 454; D000409:Alanine