Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors

J Med Chem. 1999 May 20;42(10):1749-56. doi: 10.1021/jm980667k.

Abstract

A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. The evolution from the photochemically unstable bisamidine (Z,Z)-BABCH to potent bisamidine compounds with a pyridine heterocycle as the core scaffold has been achieved. The most potent compound in the series, 6h, has a Ki for human factor Xa of 12 nM. The selectivity of 6h against bovine trypsin and human thrombin was greater than 90- and 1000-fold, respectively. Two proposed modes of binding of 6h to factor Xa are made based on the crystal structures of 6h by itself and of 6h bound to bovine trypsin.

MeSH terms

  • Amidines / chemical synthesis*
  • Amidines / chemistry
  • Animals
  • Cattle
  • Crystallography, X-Ray
  • Drug Design
  • Factor Xa Inhibitors*
  • Fibrinolytic Agents / chemical synthesis*
  • Fibrinolytic Agents / chemistry
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thrombin / antagonists & inhibitors
  • Trypsin Inhibitors / chemical synthesis
  • Trypsin Inhibitors / chemistry

Substances

  • 3,3'-(3,5-difluoro-4-methyl-2,6-pyridinediylbis(oxy))bis(benzenecarbox(imide)amide)
  • Amidines
  • Factor Xa Inhibitors
  • Fibrinolytic Agents
  • Pyridines
  • Trypsin Inhibitors
  • Thrombin