Wong P C, Crain E J, Knabb R M, Meade R P, Quan M L, Watson C A, Wexler R R, Wright M R, Slee A M
Cardiovascular Diseases Research, DuPont Pharmaceuticals Company, Wilmington, Delaware, USA.
J Pharmacol Exp Ther. 2000 Oct;295(1):212-8.
SK549 (mol. wt. 546 Da) is a synthetic, selective inhibitor of human coagulation factor Xa (fXa) (K(i) = 0.52 nM). This study compared the antithrombotic effects of SK549 and a series of benzamidine isoxazoline fXa inhibitors with aspirin, DuP 714 (a direct thrombin inhibitor), recombinant tick anticoagulant peptide, or heparin in a rabbit model of electrically induced carotid arterial thrombosis. Compounds were infused i.v. continuously from 60 min before electrical stimulation to the end of the experiment. Values of ED(50) (dose that increases the carotid blood flow to 50% of the control) were 0.12 micromol/kg/h for SK549, 0.56 micromol/kg/h for aspirin, 0.14 micromol/kg/h for DuP 714, 0.06 micromol/kg/h for recombinant tick anticoagulant peptide, and >100 U/kg/h for heparin. The EC(50) (plasma concentration that increased blood flow to 50% of the control) for SK549 was 97 nM. Unlike aspirin and heparin, SK549 was efficacious and, at 1.5 micromol/kg/h i.v. (n = 9), maintained carotid blood flow at 87 +/- 6% of control level for greater than 90 min. Unlike heparin, SK549 inhibited ex vivo fXa activity but not ex vivo thrombin activity. There was a highly significant correlation between K(i) (fXa) and ED(50) of a series of fXa inhibitors (r = 0. 85, P <.001). Therefore, these results suggest that SK549 is a novel, potent, and effective antithrombotic agent in a rabbit model of arterial thrombosis. It is likely that SK549 exerts its antithrombotic effect through selective inhibition of fXa. Furthermore, SK549 may be clinically useful for the prevention of arterial thrombosis.
SK549（分子量546道尔顿）是一种人工合成的人凝血因子Xa（fXa）选择性抑制剂（抑制常数Ki = 0.52纳摩尔）。本研究在电诱导颈动脉血栓形成的兔模型中，比较了SK549和一系列苯甲脒异恶唑啉fXa抑制剂与阿司匹林、DuP 714（一种直接凝血酶抑制剂）、重组蜱抗凝肽或肝素的抗血栓形成作用。化合物从电刺激前60分钟开始静脉持续输注直至实验结束。SK549的半数有效剂量（ED50，使颈动脉血流量增加至对照值50%的剂量）为0.12微摩尔/千克/小时，阿司匹林为0.56微摩尔/千克/小时，DuP 714为0.14微摩尔/千克/小时，重组蜱抗凝肽为0.06微摩尔/千克/小时，肝素大于100单位/千克/小时。SK549的半数有效浓度（EC50，使血流量增加至对照值50%的血浆浓度）为97纳摩尔。与阿司匹林和肝素不同，SK549有效，静脉注射剂量为1.5微摩尔/千克/小时（n = 9）时，能使颈动脉血流量维持在对照水平的87±6%达90分钟以上。与肝素不同，SK549抑制体外fXa活性，但不抑制体外凝血酶活性。一系列fXa抑制剂的抑制常数（Ki，fXa）与半数有效剂量（ED50）之间存在高度显著的相关性（r = 0.85，P <.001）。因此，这些结果表明，在动脉血栓形成的兔模型中，SK549是一种新型、强效且有效的抗血栓形成药物。SK549可能通过选择性抑制fXa发挥其抗血栓形成作用。此外，SK549在临床上可能对预防动脉血栓形成有用。
