Design, synthesis, and structure-activity relationship of novel and effective apixaban derivatives as FXa inhibitors containing 1,2,4-triazole/pyrrole derivatives as P2 binding element

Bioorg Med Chem. 2016 Nov 1;24(21):5646-5661. doi: 10.1016/j.bmc.2016.09.024. Epub 2016 Sep 12.

Abstract

Four series of novel and potent FXa inhibitors possessing the 1,2,4-triazole moiety and pyrrole moiety as P2 binding element and dihydroimidazole/tetrahydropyrimidine groups as P4 binding element were designed, synthesized, and evaluated for their anticoagulant activity in human and rabbit plasma in vitro. Most compounds showed moderate to excellent activity. Compounds 14a, 16, 18c, 26c, 35a, and 35b were further examined for their inhibition activity against human FXa in vitro and rat venous thrombosis in vivo. The most promising compound 14a, with an IC50 (FXa) value of 0.15μM and 99% inhibition rate, was identified for further evaluation as an FXa inhibitor.

Keywords: Anticoagulant activity; FXa; Structure–activity relationships; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Factor Xa / metabolism*
  • Factor Xa Inhibitors / chemical synthesis
  • Factor Xa Inhibitors / chemistry
  • Factor Xa Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyridones / chemical synthesis*
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Rabbits
  • Rats
  • Structure-Activity Relationship
  • Triazoles / chemistry
  • Triazoles / pharmacology*
  • Venous Thrombosis / drug therapy

Substances

  • Factor Xa Inhibitors
  • Pyrazoles
  • Pyridones
  • Pyrroles
  • Triazoles
  • 1,2,4-triazole
  • apixaban
  • Factor Xa