Discovery of BAY 3389934 Hydrochloride: A Potent and Selective Small-Molecule Dual Factor IIa/Xa Inhibitor with Short Half-Life for the Acute Treatment of Sepsis-Induced Coagulopathy

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 (31), a potent and highly selective, direct
dual FIIa/Xa inhibitor, with high solubility suited for i.v. 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 (t1/2), resulting in a high
controllability of the pharmacological action.