Ferraboschi Patrizia, Colombo Diego, Legnani Laura, Toma Lucio, Grisenti Paride, Vistoli Giulio, Meneghetti Fiorella
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy.
Chirality. 2013 Dec;25(12):871-82. doi: 10.1002/chir.22228. Epub 2013 Aug 22.
Argatroban (I), a potent noncovalent reversible thrombin inhibitor, is used as an anticoagulant for the parenteral treatment of heparin-induced thrombocytopenia (HIT) patients. By virtue of its pharmacological properties and the well-balanced risks and benefits, argatroban is now emerging as a clinically relevant antithrombotic agent. The availability of this drug as a mixture of 21R and 21S-diastereoisomers, in a ratio of roughly 64:36, prompted us to design an efficient separation setup of the two epimers. We pursued our efforts on their detailed structural analysis with the aim of understanding their different activity and aqueous solubility. These investigations were accompanied by a modeling study of the two diastereoisomers, with particular attention on the easy interconverting half-chair of the tetrahydroquinoline system and its preferred conformation, which is determined by the configuration at C21. These results, together with the analysis of their physicochemical profiles, provide new useful information for the development of the individual diastereoisomers.
阿加曲班（I）是一种强效的非共价可逆凝血酶抑制剂，用作肝素诱导的血小板减少症（HIT）患者肠外治疗的抗凝剂。凭借其药理特性以及良好平衡的风险和益处，阿加曲班正逐渐成为一种具有临床相关性的抗血栓形成药物。该药物以21R和21S-非对映异构体的混合物形式存在，比例约为64:36，这促使我们设计一种高效的两种差向异构体分离装置。我们致力于对它们进行详细的结构分析，旨在了解它们不同的活性和水溶性。这些研究伴随着对两种非对映异构体的建模研究，特别关注四氢喹啉系统易于相互转化的半椅式构象及其优选构象，其由C21处的构型决定。这些结果，连同对它们物理化学特征的分析，为开发单个非对映异构体提供了新的有用信息。
