Heran C, Morgan S, Kasiewski C, Bostwick J, Bentley R, Klein S, Chu V, Brown K, Colussi D, Czekaj M, Perrone M, Leadley R
Cardiovascular Drug Discovery, Rhône-Poulenc Rorer, Mail Stop NW4, 500 Arcola Road, Collegeville, PA, USA.
Eur J Pharmacol. 2000 Feb 18;389(2-3):201-7. doi: 10.1016/s0014-2999(99)00902-4.
Coagulation factor Xa is the sole enzyme responsible for activating the zymogen prothrombin to thrombin, resulting in fibrin generation, platelet activation, and subsequent thrombus formation. Our objective was to evaluate the antithrombotic efficacy of the novel factor Xa inhibitor, 2-(3-carbamimidoyl-benzyl)-3-[(3', 4'dimethoxy-biphenyl-4-carbonyl)-amino]-butyric acid methyl ester-trifluoroacetate (RPR208566), in a well-established rat model of arterial thrombosis, and to compare the results with those obtained with argatroban and heparin, direct and indirect inhibitors of thrombin, respectively. Thrombus formation was initiated by placing a filter paper saturated with FeCl(2) on the adventia of the carotid artery for 10 min. Time-to-occlusion was measured from initiation of injury until blood flow reached zero. Formed thrombi were removed and weighed 60 min after the placement of the filter paper. RPR208566, heparin, and argatroban dose-dependently increased time-to-occlusion and reduced thrombus mass. When administered at 500 microgram/kg+50 microgram/kg/min, RPR208566 prolonged time-to-occlusion to 56+/-4 min (vs. 18+/-2 min for vehicle) and reduced thrombus mass to 3.0+/-0.7 mg (vs. 7.3+/-0.6 mg for vehicle). The highest doses of argatroban (500 microgram/kg+50 microgram/kg/min) and heparin (300 U/kg+10 U/kg/min) increased time-to-occlusion to the maximum of 60 min and decreased thrombus mass to 5.5+/-0.8 and 2.6+/-0.3, respectively. The antithrombotic effects of heparin and argatroban at these doses were associated with increases in activated partial thromboplastin time of 5.6+/-0.9- and 2.9+/-0.3-fold over baseline, respectively. However, the highest dose of RPR208566 produced a modest 1.3+/-0.1-fold increase in activated partial thromboplastin time. These results indicate that factor Xa inhibition with compounds such as RPR208566 may be an attractive mechanism for novel antithrombotic drug therapy.
凝血因子Xa是唯一负责将凝血酶原激活为凝血酶的酶，从而导致纤维蛋白生成、血小板激活以及随后的血栓形成。我们的目的是在一个成熟的大鼠动脉血栓形成模型中评估新型因子Xa抑制剂2-(3-氨甲酰亚胺基苄基)-3-[(3',4'-二甲氧基联苯-4-羰基)-氨基]-丁酸甲酯-三氟乙酸盐（RPR208566）的抗血栓形成功效，并将结果与分别作为凝血酶直接和间接抑制剂的阿加曲班和肝素所获得的结果进行比较。通过将浸有FeCl₂的滤纸放置在颈动脉外膜上10分钟来引发血栓形成。从损伤开始到血流达到零来测量闭塞时间。在放置滤纸60分钟后取出形成的血栓并称重。RPR208566、肝素和阿加曲班均剂量依赖性地增加闭塞时间并减少血栓质量。当以500微克/千克 + 50微克/千克/分钟给药时，RPR208566将闭塞时间延长至56 ± 4分钟（相对于溶媒对照组为18 ± 2分钟），并将血栓质量减少至3.0 ± 0.7毫克（相对于溶媒对照组为7.3 ± 0.6毫克）。阿加曲班（500微克/千克 + 50微克/千克/分钟）和肝素（300单位/千克 + 10单位/千克/分钟）的最高剂量将闭塞时间延长至最大60分钟，并分别将血栓质量减少至5.5 ± 0.8毫克和2.6 ± 0.3毫克。这些剂量下肝素和阿加曲班的抗血栓形成作用分别与活化部分凝血活酶时间比基线增加5.6 ± 0.9倍和2.9 ± 0.3倍相关。然而，RPR208566的最高剂量使活化部分凝血活酶时间适度增加了1.3 ± 0.1倍。这些结果表明，用RPR208566等化合物抑制因子Xa可能是新型抗血栓药物治疗的一个有吸引力的机制。
