Design, synthesis, and biological activity of non-basic compounds as factor Xa inhibitors: SAR study of S1 and aryl binding sites

Bioorg Med Chem. 2005 Jun 2;13(12):3927-54. doi: 10.1016/j.bmc.2005.04.006.

Abstract

Compound 7 was identified as the active metabolite of 6 by HPLC and mass spectral analysis. Modification of lead compound 7 by transformation of its N-oxide 6-6 biaryl ring system and fused aromatics produced a series of non-basic fXa inhibitors with excellent potency in anti-fXa and anticoagulant assays. The optimized compounds 73b and 75b showed sub to one digit micromolar anticoagulant activity (PTCT2). Particularly, anti-fXa activity was detected in plasma of rats orally administered with 1mg/kg of compound 75b.

MeSH terms

  • Administration, Oral
  • Animals
  • Anticoagulants / chemical synthesis*
  • Anticoagulants / pharmacology
  • Binding Sites
  • Blood Coagulation / drug effects
  • Blood Coagulation Tests
  • Drug Design
  • Factor Xa Inhibitors*
  • Humans
  • Intestinal Absorption
  • Rats
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / pharmacokinetics*
  • Serine Proteinase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Anticoagulants
  • Factor Xa Inhibitors
  • Serine Proteinase Inhibitors