Design and synthesis of potent, selective phenylimidazole-based FVIIa inhibitors

Bioorg Med Chem Lett. 2015;25(10):2169-73. doi: 10.1016/j.bmcl.2015.03.062. Epub 2015 Mar 30.

Abstract

Heterocyclic amide isosteres were incorporated into a phenylglycine-based tissue factor/factor VIIa (TF-FVIIa) inhibitor chemotype, providing potent inhibitors. An X-ray co-crystal structure of phenylimidazole 19 suggested that an imidazole nitrogen atom effectively mimics an amide carbonyl, while the phenyl ring forms key hydrophobic interactions with the S1' pocket. Exploration of phenylimidazole substitution led to the discovery of potent, selective and efficacious inhibitors of TF-FVIIa.

Keywords: Amide isosteres; Factor VIIa; Serine protease inhibitors; TF–FVIIa inhibitor; Tissue factor.

MeSH terms

  • Crystallography, X-Ray
  • Drug Design*
  • Factor VIIa / antagonists & inhibitors*
  • Imidazoles / chemistry*
  • Molecular Structure
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*

Substances

  • Imidazoles
  • Serine Proteinase Inhibitors
  • Factor VIIa