de Kort Martin, Buijsman Rogier C, van Boeckel Constant A A
NV Organon, Molenstraat 110, 5340 BH, Oss, The Netherlands.
Drug Discov Today. 2005 Jun 1;10(11):769-79. doi: 10.1016/S1359-6446(05)03457-4.
The journey towards a detailed mechanistic understanding of the anticoagulant action of heparin has resulted in synthetic mimetics with improved pharmacodynamic profiles. Inspired by the ternary complex formation of heparin with antithrombin III and thrombin, the active pentasaccharide fondaparinux has been succeeded by several clinical candidates, such as SR123781, that have tailor-made factor Xa and thrombin inhibitory activities combined with less aspecific binding (e.g. binding to platelet factor 4 involved in thrombocytopenia). Novel compounds with both antithrombin III-mediated inhibition of factor Xa and direct thrombin inhibition are emerging. Org42675 is one such compound, balancing dual inhibition of factor Xa and thrombin in one anticoagulant drug, with excellent pharmacokinetic properties and strong inhibitory activity toward clot-bound thrombin.
在深入理解肝素抗凝作用机制的征程中，已研发出具有改善药效学特性的合成模拟物。受肝素与抗凝血酶III和凝血酶形成三元复合物的启发，活性五糖磺达肝癸钠之后出现了多个临床候选药物，如SR123781，它们具有量身定制的因子Xa和凝血酶抑制活性，且非特异性结合较少（如与血小板减少症中涉及的血小板因子4的结合）。同时，兼具抗凝血酶III介导的因子Xa抑制作用和直接凝血酶抑制作用的新型化合物也不断涌现。Org42675就是这样一种化合物，它在一种抗凝药物中平衡了因子Xa和凝血酶的双重抑制作用，具有出色的药代动力学特性以及对凝块结合型凝血酶的强大抑制活性。
