Neutral macrocyclic factor VIIa inhibitors

Bioorg Med Chem Lett. 2017 Jun 15;27(12):2650-2654. doi: 10.1016/j.bmcl.2017.04.008. Epub 2017 Apr 19.

Abstract

Factor VIIa (FVIIa) inhibitors have shown strong antithrombotic efficacy in preclinical thrombosis models with limited bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful due to the requirement of a basic P1 group to interact with Asp189 in the S1 binding pocket, limiting their membrane permeability. We have combined recently reported neutral P1 binding substituents with a highly optimized macrocyclic chemotype to produce FVIIa inhibitors with low nanomolar potency and enhanced permeability.

Keywords: Anticoagulant; Macrocycles; Neutral P1; TF-FVIIa.

MeSH terms

  • Dose-Response Relationship, Drug
  • Factor VIIa / antagonists & inhibitors*
  • Humans
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacology*
  • Molecular Structure
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Macrocyclic Compounds
  • Serine Proteinase Inhibitors
  • Factor VIIa