Orally active zwitterionic factor Xa inhibitors with long duration of action

Bioorg Med Chem Lett. 2011 Dec 15;21(24):7337-43. doi: 10.1016/j.bmcl.2011.10.021. Epub 2011 Oct 13.

Abstract

We have optimized 2-aminomethylphenylamine derivative as a factor Xa inhibitor. Several polar functional groups were introduced in the central phenyl ring, and we focused on zwitter ionic compound showing continuous inhibitory activity in oral administration test. In vitro and oral activities were improved by optimization of S1 and S4 ligands. Incorporating the interaction with S1-β pocket enhanced in vitro factor Xa inhibitory activity to less than 1 nM. Many zwitter ionic compounds showed long duration of action and potent inhibitory activity and high AUC values in oral administration tests to monkeys.

MeSH terms

  • Administration, Oral
  • Aniline Compounds / chemical synthesis
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacokinetics
  • Animals
  • Anticoagulants / chemical synthesis
  • Anticoagulants / chemistry*
  • Anticoagulants / pharmacokinetics
  • Binding Sites
  • Computer Simulation
  • Factor Xa / metabolism
  • Factor Xa Inhibitors*
  • Haplorhini
  • Ions / chemistry
  • Protein Structure, Tertiary
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / pharmacokinetics
  • Structure-Activity Relationship

Substances

  • 2-aminomethylphenylamine
  • Aniline Compounds
  • Anticoagulants
  • Factor Xa Inhibitors
  • Ions
  • Serine Proteinase Inhibitors
  • Factor Xa