Nonbenzamidine acylsulfonamide tissue factor-factor VIIa inhibitors

Bioorg Med Chem Lett. 2013 Sep 15;23(18):5244-8. doi: 10.1016/j.bmcl.2013.06.027. Epub 2013 Jun 21.


Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P' binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype.

Keywords: Factor VIIa; Serine protease inhibitors; Structure-based design; TF-FVIIa inhibitor; Tissue factor.

MeSH terms

  • Benzamidines*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Factor VIIa / antagonists & inhibitors*
  • Factor VIIa / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology*


  • Benzamidines
  • Serine Proteinase Inhibitors
  • Sulfonamides
  • Factor VIIa