Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors IV. A series of new derivatives containing a spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one skeleton

Chem Pharm Bull (Tokyo). 2004 Apr;52(4):406-12. doi: 10.1248/cpb.52.406.

Abstract

In the course of development of factor Xa (FXa) inhibitor in an investigation involving the synthesis of 1-arylsulfonyl-3-piperazinone derivatives, we found new compounds containing a unique spiro skeleton. Among such compounds, (-)-7-[(6-chloro-2-naphthalenyl)sulfonyl]tetrahydro-8a-(methoxymethyl)-1'-(4-pyridinyl)-spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one (28, M55529) had activity more favorable than those of previously reported compounds. The inhibitory activity of M55529 for FXa is IC(50)=2 nM, with high selectivity for FXa over thrombin and trypsin.

MeSH terms

  • Crystallography, X-Ray
  • Cyclization
  • Factor Xa Inhibitors*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology*
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship
  • Thrombin / antagonists & inhibitors
  • Trypsin Inhibitors / chemical synthesis
  • Trypsin Inhibitors / pharmacology

Substances

  • Factor Xa Inhibitors
  • M55529
  • Pyridines
  • Spiro Compounds
  • Trypsin Inhibitors
  • Thrombin