Wong Pancras C, Crain Earl J, Watson Carol A, Zaspel Alverna M, Wright Matthew R, Lam Patrick Y, Pinto Donald J P, Wexler Ruth R, Knabb Robert M
Cardiovascular Biology, Bristol-Myers Squibb Company, Wilmington, Delaware 19880-0400, USA.
J Pharmacol Exp Ther. 2002 Dec;303(3):993-1000. doi: 10.1124/jpet.102.040089.
DPC423 [1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide] is a synthetic, competitive, and selective inhibitor of coagulation factor Xa (fXa) (K(i): 0.15 nM in humans, 0.3 nM in rabbit). The objective of this study was to compare effects of DPC423, enoxaparin (low-molecular-weight heparin), and argatroban (thrombin inhibitor) on arterial thrombosis and hemostasis in rabbit models of electrically induced carotid artery thrombosis and cuticle bleeding, respectively. Compounds were infused i.v. continuously from 60 min before artery injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. Antithrombotic ED(50) values were 0.4 mg/kg/h for enoxaparin (n = 6), 0.13 mg/kg/h for argatroban (n = 6), and 0.6 mg/kg/h for DPC423 (n = 12). DPC423 at the maximum antithrombotic dose increased activated partial thromboplastin time and prothrombin time (n = 6) by 1.8 +/- 0.07- and 1.8 +/- 0.13-fold, respectively, without changes in thrombin time and ex vivo thrombin activity. The antithrombotic effect of DPC423 was significantly correlated with its ex vivo anti-fXa activity (r = 0.86). DPC423 at 1, 3, and 10 mg/kg p.o. increased carotid blood flow (percent control) at 45 min to 10 +/- 4, 24 +/- 6, and 74 +/- 7, respectively (n = 6/group). Cuticle bleeding times (percent change over control) determined at the maximum antithrombotic dose were 88 +/- 12 for argatroban, 69 +/- 13 for heparin, 4 +/- 3 for enoxaparin, 5 +/- 4 for DPC423, and -3 +/- 2 for the vehicle (n = 5-6/group), suggesting dissociation of antithrombotic and bleeding time effects for DPC423 and enoxaparin. The combination of aspirin and DPC423 at ineffective antithrombotic doses produced significant antithrombotic effect. Therefore, these results suggest that DPC423 is a clinically useful oral anticoagulant for the prevention of arterial thrombosis.
DPC423 [1-[3-(氨甲基)苯基]-N-[3-氟-2'-(甲基磺酰基)[1,1'-联苯]-4-基]-3-(三氟甲基)-1H-吡唑-5-甲酰胺] 是一种合成的、竞争性的、选择性凝血因子Xa（fXa）抑制剂（人源K(i)：0.15 nM，兔源K(i)：0.3 nM）。本研究的目的是分别比较DPC423、依诺肝素（低分子量肝素）和阿加曲班（凝血酶抑制剂）对电诱导颈动脉血栓形成兔模型和表皮出血兔模型中动脉血栓形成和止血的影响。化合物在动脉损伤或表皮横切前60分钟开始静脉持续输注直至实验结束。颈动脉血流用作抗血栓形成作用的标志物。依诺肝素（n = 6）的抗血栓形成ED(50)值为0.4 mg/kg/h，阿加曲班（n = 6）为0.13 mg/kg/h，DPC423（n = 12）为0.6 mg/kg/h。DPC423在最大抗血栓形成剂量下使活化部分凝血活酶时间和凝血酶原时间（n = 6）分别增加1.8±0.07倍和1.8±0.13倍，而凝血酶时间和体外凝血酶活性无变化。DPC423的抗血栓形成作用与其体外抗fXa活性显著相关（r = 0.86）。DPC423口服1、3和10 mg/kg时，45分钟时颈动脉血流（相对于对照组的百分比）分别增加至10±4、24±6和74±7（n = 6/组）。在最大抗血栓形成剂量下测定的表皮出血时间（相对于对照组的变化百分比），阿加曲班为88±12，肝素为69±13，依诺肝素为4±3，DPC423为5±4，溶剂组为-3±2（n = 5 - 6/组），表明DPC423和依诺肝素的抗血栓形成作用与出血时间效应分离。阿司匹林和DPC423在无效抗血栓形成剂量下联合使用产生了显著的抗血栓形成作用。因此，这些结果表明DPC423是一种临床上用于预防动脉血栓形成的有效口服抗凝剂。
