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

  • J Med Chem. 2025 Jun 26;68(12):12687-12707. doi: 10.1021/acs.jmedchem.5c00538.
Hartmut Beck  1 ,  Stefanie Mesch  2 ,  Stefanie Zimmermann  1 ,  Alexandros Vakalopoulos  1 ,  Lutz Lehmann  1 ,  Kersten Matthias Gericke  1 ,  Frank Süßmeier  1 ,  Lars Baerfacker  1 ,  Alexander Hillisch  3 ,  Katharina Meier  1 ,  Adrian Tersteegen  1 ,  Anja Buchmüller  1 ,  Christoph Gerdes  1 ,  Julia Dietze-Torres  1 ,  Elisabeth Kersten  1 ,  Katrin Partikel  1 ,  Andreas Bröhl  1 ,  Guillaume Levilain  4 ,  Stefan Heitmeier  1 ,  Nils Pfaff  1 ,  Markus Follmann  1
Affiliations
  • 1. Bayer AG, Pharmaceuticals, Research & Development, 42113 Wuppertal, Germany.
  • 2. F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
  • 3. UCB BioSciences GmbH, 40789 Monheim, Germany.
  • 4. Sanofi, 45 Chemin de Météline, 04200 Sisteron, France.
PMID: 40498640 DOI: 10.1021/acs.jmedchem.5c00538
Abstract

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.

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