Peternel Luka, Stegnar Mojca, Drevensek Gorazd, Budihna Metka V, Bozic Mojca, Zega Anamarija, Stalc Anton, Cerne Manica, Urleb Uros
Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia.
Thromb Haemost. 2005 Mar;93(3):437-42. doi: 10.1160/TH04-10-0676.
The antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold (LK-732, LK-639 and LK-731) and their amidoxime prodrugs (LK-658, LK-633 and LK-730) was studied in comparison to argatroban and nadroparin in two rat models of venous thrombosis, induced either by complete stasis combined with hypercoagulability (model 1) or by partial stasis combined with vessel injury (model 2). In initial experiments LK-732 was established as the most promising antithrombotic of the LK inhibitors and as such was further tested. In model 1, intravenous bolus administration of LK-732 produced a dose-dependent inhibition of thrombus formation with an ID50 value of 1.3 mg/kg. This ID50 value was approximately four times higher than the ID50 value of argatroban (0.3 mg/kg; p=0.011). However, in model 2, LK-732 and argatroban decreased thrombus weight by 50% at similar ID50 values (3.8 mg/kg vs 3.0 mg/kg, respectively; p=0.726). The ex vivo anticoagulant effect of LK-732 was substantially weaker compared to argatroban at doses that produced comparable antithrombotic effects. After subcutaneous administration, in vivo thrombus weight reduction of LK inhibitors (10 mg/kg) ranged between 22 to 48%. However, their oral antithrombotic effect at a dose of 30 mg/kg was rather low. LK amidoxime prodrugs failed to produce a substantial antithrombotic effect after subcutaneous (10 mg/kg) as well as after oral administration (30 mg/kg). In conclusion, thrombin inhibitors built on the azaphenylalanine scaffold represent a new group of intravenously effective antithrombotics. However, optimisation of the oral antithrombotic effect of amidoxime prodrug LK-658 of the lead inhibitor LK-732 is required for justifying further development of these inhibitors.
研究了基于氮杂苯丙氨酸支架构建的新型直接凝血酶抑制剂（LK-732、LK-639和LK-731）及其偕胺肟前药（LK-658、LK-633和LK-730）与阿加曲班和那屈肝素相比，在两种大鼠静脉血栓形成模型中的抗血栓形成潜力。这两种模型分别是由完全淤滞联合高凝状态诱导的（模型1），以及由部分淤滞联合血管损伤诱导的（模型2）。在初步实验中，LK-732被确定为LK抑制剂中最有前景的抗血栓药物，并因此进行了进一步测试。在模型1中，静脉推注LK-732可产生剂量依赖性的血栓形成抑制作用，ID50值为1.3mg/kg。该ID50值约为阿加曲班ID50值（0.3mg/kg；p=0.011）的四倍。然而，在模型2中，LK-732和阿加曲班在相似的ID50值（分别为3.8mg/kg和3.0mg/kg；p=0.726）下使血栓重量降低了50%。在产生相当抗血栓作用的剂量下，LK-732的体外抗凝作用与阿加曲班相比明显较弱。皮下给药后，LK抑制剂（10mg/kg）的体内血栓重量减少范围在22%至48%之间。然而，它们在30mg/kg剂量下的口服抗血栓作用相当低。LK偕胺肟前药在皮下（10mg/kg）以及口服给药（30mg/kg）后均未产生显著的抗血栓作用。总之，基于氮杂苯丙氨酸支架构建的凝血酶抑制剂代表了一类新的静脉内有效的抗血栓药物。然而，为了证明这些抑制剂的进一步开发是合理的，需要优化先导抑制剂LK-732的偕胺肟前药LK-658的口服抗血栓作用。
