Raake W, Klauser R J, Elling H, Zeiller P, Meinetsberger E
Department of Chemistry, Luitpold Pharma, Munich, Germany.
Semin Thromb Hemost. 1994;20(2):176-81. doi: 10.1055/s-2007-1001901.
Aprosulate sodium was the first representative of a new class of synthetic polyanions showing antithrombotic efficacy in different animal models. In several clinical trails (Phase I) in human volunteers aprosulate demonstrated anticoagulant properties, too. Searching for other active substances of similar structure, a series of bis-aldonic acid amides were synthesized. These compounds exhibited interesting antithrombotic and anticoagulant activities. The pharmacodynamic activities of the compounds LW 10121, LW 10125, LW 10114, 10244, and LW 10168 are summarized in this article. These substances prolonged the APTT to 150% of the blank values at concentrations of 1.5 to 13.5 micrograms/mL. The thrombin time and anti-Xa test were only slightly influenced by concentrations up to 100 micrograms/mL. All compounds were investigated in a jugular vein hemostasis model in rats to examine their antithrombotic potential. They all had an antithrombotic activity lower than aprosulate, except compound LW 10121, which seemed to be a little more active. The subcutaneous injection of 10 mg/kg LW 10121 resulted in a longer duration of action than aprosulate and heparin. On the basis of the chemical structure and the profile of action, it is assumed that the new compounds may possess the same mode of action as aprosulate, but the mechanism of action may be different from heparin and low molecular weight heparins.
阿丙磺酸钠是一类新型合成聚阴离子的首个代表药物，在不同动物模型中均显示出抗血栓形成的功效。在针对人类志愿者的多项临床试验（I期）中，阿丙磺酸钠也表现出了抗凝特性。为了寻找其他具有相似结构的活性物质，合成了一系列双醛糖酸酰胺。这些化合物展现出了有趣的抗血栓形成和抗凝活性。本文总结了化合物LW 10121、LW 10125、LW 10114、10244和LW 10168的药效学活性。这些物质在浓度为1.5至13.5微克/毫升时，可将活化部分凝血活酶时间延长至空白值的150%。凝血酶时间和抗Xa试验在浓度高达100微克/毫升时仅受到轻微影响。所有化合物均在大鼠颈静脉止血模型中进行了研究，以考察它们的抗血栓形成潜力。除化合物LW 10121似乎活性稍高外，它们的抗血栓形成活性均低于阿丙磺酸钠。皮下注射10毫克/千克的LW 10121，其作用持续时间比阿丙磺酸钠和肝素更长。基于化学结构和作用特征，推测这些新化合物可能具有与阿丙磺酸钠相同的作用方式，但作用机制可能与肝素和低分子量肝素不同。
