Synthesis and P1' SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors

Bioorg Med Chem Lett. 2016 Oct 15;26(20):5051-5057. doi: 10.1016/j.bmcl.2016.08.088. Epub 2016 Aug 28.


Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity.

Keywords: Anticoagulant; Factor VIIa-TF inhibitor; Macrocycle; Thrombosis.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Dogs
  • Drug Design
  • Factor VIIa / antagonists & inhibitors*
  • Humans
  • Macrocyclic Compounds / chemical synthesis*
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacokinetics
  • Macrocyclic Compounds / pharmacology*
  • Structure-Activity Relationship
  • Thromboplastin / antagonists & inhibitors*


  • Macrocyclic Compounds
  • Thromboplastin
  • Factor VIIa