Rational design, synthesis, and biological activity of benzoxazinones as novel factor Xa inhibitors

J Med Chem. 2000 Nov 2;43(22):4063-70. doi: 10.1021/jm000074l.

Abstract

Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. From a high-throughput in vitro mass screen of our chemical library, we identified 4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-2-phenyl-2H-1, 4-benzoxazin-3(4H)-one (1a) as an inhibitor of FXa with an IC(50) of 27 microM. Through a combination of SAR studies and molecular modeling, we synthesized 3-(4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl)-1-benzenecarboximidamide (1n) which was a potent FXa inhibitor with an IC(50) of 3 nM. This compound exhibited high selectivity for FXa over other related serine proteases and was efficacious when dosed intravenously in rabbit and dog antithrombotic models.

MeSH terms

  • Administration, Oral
  • Amidines / chemical synthesis*
  • Amidines / chemistry
  • Amidines / pharmacology
  • Animals
  • Benzoxazines
  • Biological Availability
  • Combinatorial Chemistry Techniques
  • Dogs
  • Drug Design
  • Factor Xa Inhibitors*
  • Fibrinolysin / antagonists & inhibitors
  • Fibrinolytic Agents / chemical synthesis*
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / pharmacology
  • Injections, Intravenous
  • Models, Molecular
  • Oxazines / chemical synthesis*
  • Oxazines / chemistry
  • Oxazines / pharmacology
  • Rabbits
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Thrombin / antagonists & inhibitors
  • Trypsin Inhibitors / chemical synthesis
  • Trypsin Inhibitors / chemistry
  • Trypsin Inhibitors / pharmacology

Substances

  • 3-(4-(5-(2,6-dimethyltetrahydro-1(2H)-pyridinyl)pentyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-benzenecarboximidamide
  • Amidines
  • Benzoxazines
  • Factor Xa Inhibitors
  • Fibrinolytic Agents
  • Oxazines
  • Serine Proteinase Inhibitors
  • Trypsin Inhibitors
  • Thrombin
  • Fibrinolysin