Nonpeptide Factor Xa Inhibitors III: Effects of DPC423, an Orally-Active Pyrazole Antithrombotic Agent, on Arterial Thrombosis in Rabbits
Nonpeptide Factor Xa Inhibitors III: Effects of DPC423, an Orally-Active Pyrazole Antithrombotic Agent, on Arterial Thrombosis in Rabbits
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非肽因子 Xa 抑制剂 III：口服活性吡唑抗血栓药物 DPC423 对家兔动脉血栓形成的影响
DOI：
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发表时间：
2002
影响因子：
3.5
通讯作者：
R. Knabb
中科院分区：
文献类型：
--
作者：
P. Wong;E. Crain;C. Watson;Alverna M. Zaspel;M. Wright;P. Lam;D. Pinto;R. Wexler;R. Knabb
DPC423[1-[3-（氨基甲基）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-羧酰胺]是一种合成的竞争性选择性凝血因子Xa （fXa）抑制剂（K i：人0.15 nM，兔0.3 nM）。本研究的目的是比较DPC423、依诺肝素（低分子肝素）和阿加曲班（凝血酶抑制剂）对兔电致颈动脉血栓形成和角质层出血模型动脉血栓形成和止血的影响。从动脉损伤或横断角质层前60分钟开始，连续静脉滴注化合物至实验结束。颈动脉血流量作为抗血栓作用的标志。抗血栓ED50值依诺肝素为0.4 mg/kg/h (n = 6)，阿加曲班为0.13 mg/kg/h (n = 6)， DPC423为0.6 mg/kg/h （n = 12）。最大抗栓剂量的DPC423使活化的部分凝血活酶时间和凝血酶原时间（n = 6）分别增加了1.8±0.07-和1.8±0.13倍，而凝血酶时间和体外凝血酶活性没有变化。DPC423的抗血栓作用与其体外抗fxa活性显著相关（r = 0.86）。1、3和10 mg/kg p.o.的DPC423使45分钟颈动脉血流量（百分比对照）分别增加到10±4、24±6和74±7 （n= 6/组）。在最大抗血栓剂量下测定的角质层出血次数（相对于对照组的百分比变化）为阿加曲班88±12次，肝素69±13次，依诺肝素4±3次，DPC423 5±4次，载药组- 3±2次（n = 5 - 6/组），提示DPC423和依诺肝素的抗血栓作用和出血时间分离作用。阿司匹林和DPC423在无效抗栓剂量下联用可产生显著的抗栓作用。因此，这些结果表明，DPC423是一种临床上有用的口服抗凝剂，可以预防动脉血栓形成。
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 ED50 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.
影响因子：
2.9
作者：
DAVIE, EW;FUJIKAWA, K;KISIEL, W
通讯作者：
KISIEL, W