Factor VIIa inhibitors: gaining selectivity within the trypsin family

Bioorg Med Chem Lett. 2006 Mar 15;16(6):1596-600. doi: 10.1016/j.bmcl.2005.12.040. Epub 2006 Jan 18.

Abstract

Within the trypsin family of coagulation proteases, obtaining highly selective inhibitors of factor VIIa has been challenging. We report a series of factor VIIa (fVIIa) inhibitors based on the 5-amidino-2-(2-hydroxy-biphenyl-3-yl)-benzimidazole (1) scaffold with potency for fVIIa and high selectivity against factors IIa, Xa, and trypsin. With this scaffold class, we propose that a unique hydrogen bond interaction between a hydroxyl on the distal ring of the biaryl system and the backbone carbonyl of fVIIa lysine-192 provides a basis for enhanced selectivity and potency for fVIIa.

MeSH terms

  • Binding Sites
  • Factor VIIa / antagonists & inhibitors*
  • Factor Xa Inhibitors
  • Humans
  • Hydrogen Bonding
  • Protein Binding
  • Prothrombin / antagonists & inhibitors
  • Structure-Activity Relationship
  • Trypsin / metabolism

Substances

  • Factor Xa Inhibitors
  • Prothrombin
  • Factor VIIa
  • Trypsin