title: UR-3216: a new generation oral platelet GPIIb/IIIa antagonist.
abstract: Various oral platelet GPIIb/IIIa receptor antagonists have undergone clinical investigations, but to date without success. Various factors have been proposed to explain their failure such as low affinity for the receptor, large peak/trough ratio, low bioavailability, partial agonist activity and pro-aggregatory effect. Efforts to discover a truly effective, safe, oral antagonist led to the discovery of UR-3216 (Fig. 1). The active form of UR-3216, UR-2922, possessed a high affinity for the human platelet receptor (K(d) <1 nM) with a slow dissociation rate (k(off)= 90 min) in vitro. UR-2922 induced no ligand-induced binding sites (LIBS) expression or prothrombotic activity in human platelets, distinctly different from orbofiban and other small molecule antagonists. To date, UR-2922 is the only high affinity GPIIb/IIIa antagonist without LIBS expression. In vivo characteristics of UR-3216 showed prolonged duration of efficacy (>24 h) with its favorable pharmacokinetic profile, superior to all the other oral GPIIb/IIIa antagonists. UR-3216 showed high bioavailability, rapid bioconversion to the active form and biliary excretion. UR-3216 is a novel, orally active GPIIb/IIIa antagonist of a new generation, which has substantially improved the crucial compounding factors and will be useful for the treatment of cardiovascular diseases.
authors.affiliation: Pharmaceutical Division, Ube Laboratory, Ube Industries, Ltd., Ube, Yamaguchi 755-8633, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Aga
authors.forename: Kosuke
authors.initials: K
authors.lastname: Baba
authors.forename: Susan
authors.initials: S
authors.lastname: Tam
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoneda
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Kita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ueno
mesh_terms: D000284:Administration, Oral; D000818:Animals; D006801:Humans; D009574:Nitro Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D009574:Nitro Compounds; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; C486421:UR-2922; C486420:UR-3216