Arylsulfonamidopiperidone derivatives as a novel class of factor Xa inhibitors

Bioorg Med Chem Lett. 2011 Dec 15;21(24):7516-21. doi: 10.1016/j.bmcl.2011.06.098. Epub 2011 Jun 28.

Abstract

The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide-valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC(50) of 7 nM and EC(2×PT) of 1.7 μM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide-valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets.

MeSH terms

  • Anticoagulants / chemical synthesis
  • Anticoagulants / chemistry*
  • Anticoagulants / pharmacology
  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Activation / drug effects
  • Factor Xa / metabolism
  • Factor Xa Inhibitors*
  • Humans
  • Lactams / chemistry
  • Molecular Conformation
  • Piperidones / chemical synthesis
  • Piperidones / chemistry*
  • Piperidones / pharmacology
  • Protein Structure, Tertiary
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Anticoagulants
  • Factor Xa Inhibitors
  • Lactams
  • Piperidones
  • Serine Proteinase Inhibitors
  • valerolactam
  • Factor Xa