Institut de Recherches Servier, 11 rue des Moulineaux, 92150 Suresnes, et 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
J Med Chem. 2021 Apr 8;64(7):3897-3910. doi: 10.1021/acs.jmedchem.0c02072. Epub 2021 Mar 25.
Selective and potent inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) have the potential to increase endogenous and therapeutic fibrinolysis and to behave like profibrinolytic agents without the risk of major hemorrhage, since they do not interfere either with platelet activation or with coagulation during blood hemostasis. Therefore, TAFIa inhibitors could be used in at-risk patients for the treatment, prevention, and secondary prevention of stroke, venous thrombosis, and pulmonary embolisms. In this paper, we describe the design, the structure-activity relationship (SAR), and the synthesis of novel, potent, and selective phosphinanes and azaphosphinanes as TAFIa inhibitors. Several highly active azaphosphinanes display attractive properties suitable for further efficacy studies in thrombosis models.
选择性和有效的激活凝血酶可激活纤溶抑制物（TAFIa）抑制剂具有增加内源性和治疗性纤溶的潜力，并且表现得像纤维蛋白溶解剂而没有大出血的风险，因为它们既不干扰血小板激活也不干扰血液止血过程中的凝血。因此，TAFIa 抑制剂可用于有中风、静脉血栓形成和肺栓塞风险的患者的治疗、预防和二级预防。在本文中，我们描述了新型、有效和选择性的膦烷和氮杂膦烷作为 TAFIa 抑制剂的设计、结构-活性关系（SAR）和合成。一些高活性的氮杂膦烷显示出适合血栓模型进一步疗效研究的有吸引力的性质。
