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Beschreibung

A phenoxypyridinyl-phenylurea that acts as a highly selective P2Y1 antagonist (Ki = 6 nM against 0.5 nM [&beta,-33P]-2-MeS-ADP in competitive binding assays toward human P2Y1), while displaying much reduced or no affinity toward other P2Y family G-protein-coupled purinergic receptors (Ki = &ge,2.5 microM against 0.5 nM [&beta,-33P]-2-MeS-ADP binding toward hP2Y14, Ki >15 microM toward human P2Y2, P2Y6, P2Y11, and P2Y12). Effectively inhibits 2.5 microM ADP-induced platelet aggregation in vitro (IC50 = 2.1 microM using human platelet rich plasma) and reduces FeCl2-induced (via 10 min localized artery surface exposure to 50% FeCl2) carotid artery internal thrombus (blood clot) formation in anesthetized rats in vivo (by 68% 50 min post 10 min FeCl2 exposure, single 10 mg/kg i.v. 15 min prior to FeCl2 exposure, followed by continuous i.v. infusion at 10 mg/kg/h) with only 3.3- and 3.1-fold enhanced cuticle and mesenteric bleeding time, respectively. The same antithrombosis efficacy when achieved with the P2Y12 antagonist Clopidogrel (20 mg/kg p.o.) is reported to result in much prolonged cuticle and mesenteric bleeding time (4.1- and 8.2-fold of control level, respectively). Pharmacokinetic studies in rats indicate a moderate oral bioavailability (F = 10%, Cmax = 5.83 microM, Tmax = 2 h, T1/2 = 1.43 h, 30 mg/kg delivered with 10% cremophor:10% EtOH:80% H2O)., A phenoxypyridinyl-phenylurea that acts as a highly selective P2Y1 antagonist (Ki = 6 nM against 0.5 nM 2-MeS-ADP for human P2Y1 binding), while displaying much reduced or no affinity toward other P2Y family GPCRs (Ki = &ge,2.5 microM toward hP2Y14, Ki >15 microM toward human P2Y2, P2Y6, P2Y11, and P2Y12). Effectively inhibits 2.5 microM ADP-induced platelet aggregation in vitro (IC50 = 2.1 microM) and reduces FeCl2-induced carotid artery blood clot formation in anesthetized rats in vivo (10 mg/kg/h i.v. infusion) with much less effect toward prolonging cuticle and mesenteric bleeding time when compared to another P2Y12 antagonist Clopidogrel. Pharmackinetic studies reveal only moderate oral bioavailability in rat.