Beck Hartmut, Mesch Stefanie, Zimmermann Stefanie, Vakalopoulos Alexandros, Lehmann Lutz, Gericke Kersten Matthias, Süßmeier Frank, Baerfacker Lars, Hillisch Alexander, Meier Katharina, Tersteegen Adrian, Buchmüller Anja, Gerdes Christoph, Dietze-Torres Julia, Kersten Elisabeth, Partikel Katrin, Bröhl Andreas, Levilain Guillaume, Heitmeier Stefan, Pfaff Nils, Follmann Markus
Bayer AG, Pharmaceuticals, Research & Development, 42113 Wuppertal, Germany.
F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
J Med Chem. 2025 Jun 26;68(12):12687-12707. doi: 10.1021/acs.jmedchem.5c00538. Epub 2025 Jun 11.
Sepsis-induced coagulopathy (SIC) is a severe and frequent complication of sepsis, which is associated with high mortality in patients. So far, attempts have failed to establish a global standard of care in this difficult-to-treat indication. Anticoagulation with a dual inhibitor of the coagulation factors IIa (FIIa, thrombin) and Xa (FXa) has the potential to improve the treatment of life-threatening acute coagulation disorders, such as SIC. Herein, we describe the discovery of BAY 3389934 hydrochloride (), a potent and highly selective, direct dual FIIa/Xa inhibitor, with high solubility suited for application. This small molecule acts as a metabolically soft active pharmaceutical ingredient (API) due to a labile carboxylic ester group, which is responsible for the desired short pharmacokinetic and pharmacological half-life (), resulting in a high controllability of the pharmacological action.
脓毒症诱导的凝血病（SIC）是脓毒症一种严重且常见的并发症，与患者的高死亡率相关。到目前为止，在这种难以治疗的病症中尚未成功建立全球统一的治疗标准。使用凝血因子IIa（FIIa，凝血酶）和Xa（FXa）的双重抑制剂进行抗凝，有可能改善对危及生命的急性凝血障碍（如SIC）的治疗。在此，我们描述了盐酸BAY 3389934（）的发现，它是一种强效、高度选择性的直接双重FIIa/Xa抑制剂，具有高溶解度，适合应用。由于存在一个不稳定的羧酸酯基团，该小分子作为一种代谢性质温和的活性药物成分（API），这导致了所需的短药代动力学和药理学半衰期（），从而使药理作用具有高度可控性。
