Design, synthesis and structure-activity relationships of benzoxazinone-based factor Xa inhibitors

Bioorg Med Chem Lett. 2003 Feb 10;13(3):561-6. doi: 10.1016/s0960-894x(02)00927-7.

Abstract

A series of benzoxazinone derivatives was designed and synthesized as factor Xa inhibitors. We demonstrated that the naphthyl moiety in the aniline-based compounds 1 and 2 can be replaced with benzene-fused heterobicycles and biaryls to give factor Xa inhibitors with improved trypsin selectivity. The P4 modifications lead to monoamidines which are moderately active. The benzoxazinones 41-45 are potent against factor Xa, retain the improved trypsin selectivity of the corresponding aniline-based compounds, and show strong antithrombotic effect dose responsively.

MeSH terms

  • Aniline Compounds / chemical synthesis
  • Aniline Compounds / pharmacology
  • Animals
  • Binding, Competitive / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design
  • Factor Xa Inhibitors*
  • In Vitro Techniques
  • Indicators and Reagents
  • Models, Molecular
  • Molecular Conformation
  • Oxazines / chemical synthesis*
  • Oxazines / pharmacology*
  • Rabbits
  • Structure-Activity Relationship
  • Thrombin / metabolism
  • Trypsin Inhibitors / chemical synthesis
  • Trypsin Inhibitors / pharmacology

Substances

  • Aniline Compounds
  • Factor Xa Inhibitors
  • Indicators and Reagents
  • Oxazines
  • Trypsin Inhibitors
  • Thrombin