Design, synthesis and structure-activity relationship of oxazolidinone derivatives containing novel S4 ligand as FXa inhibitors

Eur J Med Chem. 2015:96:369-80. doi: 10.1016/j.ejmech.2015.04.025. Epub 2015 Apr 16.

Abstract

A novel series of potent and efficacious factor Xa inhibitors which possesses pyrrole/indole/thiazole moieties as S4 binding element was identified. Compound 7b showed strong human factor Xa inhibitory activity (IC50 = 2.01 nM) and anticoagulant activities in both human (PTCT2 = 0.15 μM, APPTCT2 = 0.30 μM) and rabbit plasma (PTCT2 = 0.46 μM, APPTCT2 = 0.75 μM). The SARs analyses indicated that the size and water solubility of different alkylamino group at the position of S4 ligand were responsible for the anticoagulant activity.

Keywords: Anticoagulant activity; Factor Xa inhibitors; Oxazolidinone derivatives; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticoagulants / chemical synthesis
  • Anticoagulants / chemistry
  • Anticoagulants / pharmacology*
  • Blood Coagulation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Factor Xa / metabolism*
  • Factor Xa Inhibitors / chemical synthesis*
  • Factor Xa Inhibitors / chemistry
  • Factor Xa Inhibitors / pharmacology*
  • Humans
  • Ligands
  • Molecular Structure
  • Oxazoles / chemical synthesis
  • Oxazoles / chemistry
  • Oxazoles / pharmacology*
  • Rabbits
  • Structure-Activity Relationship

Substances

  • Anticoagulants
  • Factor Xa Inhibitors
  • Ligands
  • Oxazoles
  • oxazolidine
  • Factor Xa