Highly efficacious factor Xa inhibitors containing alpha-substituted phenylcycloalkyl P4 moieties

Bioorg Med Chem Lett. 2009 Jan 15;19(2):462-8. doi: 10.1016/j.bmcl.2008.11.049. Epub 2008 Nov 18.


We previously disclosed a series of highly potent FXa inhibitors bearing alpha-substituted (CH(2)NR(1)R(2)) phenylcyclopropyl P4 moieties in the pyrazolodihydropyridone core system. Herein, we describe our continuous SAR efforts in this series. Effects of the C-3 substitution of the pyrazolodihydropyridone core and the alpha-substitution (R group) of the cyclopropyl ring on FXa binding affinity (FXa K(i)), human plasma anticoagulant activity (PT EC(2x)) and permeability are discussed. A set of compounds obtained from optimization of the R group and the C-3 substituent were orally bioavailable in dogs. Furthermore, representative compounds were highly efficacious in the rabbit arterio-venous shunt thrombosis model (EC(50)s=29-81nM).

MeSH terms

  • Animals
  • Caco-2 Cells
  • Factor Xa Inhibitors*
  • Humans
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Rabbits
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship


  • Factor Xa Inhibitors
  • Pyridones
  • Serine Proteinase Inhibitors