Synthesis and structure-activity relationship of potent, selective and orally active anthranilamide-based factor Xa inhibitors: application of weakly basic sulfoximine group as novel S4 binding element

Eur J Med Chem. 2012 Dec:58:136-52. doi: 10.1016/j.ejmech.2012.10.005. Epub 2012 Oct 16.


A novel series of potent and efficacious factor Xa inhibitors which possesses sulfoximine moiety as novel S4 binding element in anthranilamide chemotype has been identified. Lead optimization at this novel P4 group led to many potent factor Xa inhibitors with excellent anticoagulant activity in human plasma. Selected compounds were dosed orally in rats and checked for their ex vivo prothrombin time prolonging activity, which resulted in identification of compound 5-chloro-N-(5-chloropyridin-2-yl)-2-(4-(N-(2-(diethylamino)acetyl)-S-methylsulfonimidoyl)benzamido)benzamide (18f). The detailed pharmacokinetic evaluation and subsequent metabolism study of 18f suggested the presence of an active metabolite. The compound 18f and its active metabolite 18b demonstrated excellent in vivo efficacy in both arterial and venous thrombosis model in rats and were found to be highly selective against related serine proteases. Based on this promising profile, compound 18f was selected for further evaluation.

MeSH terms

  • Animals
  • Anticoagulants / administration & dosage
  • Anticoagulants / chemical synthesis
  • Anticoagulants / metabolism
  • Anticoagulants / pharmacology*
  • Binding Sites / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Factor Xa Inhibitors*
  • Humans
  • Imines / chemistry*
  • Male
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Rats, Wistar
  • Reference Values
  • Serine Proteases / metabolism
  • Serine Proteinase Inhibitors / administration & dosage
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / metabolism
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Sulfoxides / chemistry*
  • Venous Thrombosis / drug therapy
  • Venous Thrombosis / metabolism
  • ortho-Aminobenzoates / administration & dosage
  • ortho-Aminobenzoates / chemical synthesis
  • ortho-Aminobenzoates / metabolism
  • ortho-Aminobenzoates / pharmacology*


  • Anticoagulants
  • Factor Xa Inhibitors
  • Imines
  • Serine Proteinase Inhibitors
  • Sulfoxides
  • ortho-Aminobenzoates
  • Serine Proteases
  • anthranilamide