Design, synthesis, and biological activity of novel tetrahydropyrazolopyridone derivatives as FXa inhibitors with potent anticoagulant activity

Bioorg Med Chem. 2017 May 15;25(10):2800-2810. doi: 10.1016/j.bmc.2017.03.055. Epub 2017 Mar 29.

Abstract

A series of novel tetrahydropyrazolopyridone derivatives containing 1,3,4-triazole, triazolylmethyl, and partially saturated heterocyclic moieties as P2 binding element was designed, synthesized, and evaluated in vitro for anticoagulant activity in human and rabbit plasma. All compounds showed moderate to significant potency, and compounds 15b, 15c, 20b, 20c, and 22b were further examined for their inhibitory activity against human FXa in vitro. While compounds 15c and 22b were tested for rat venous thrombosis in vivo. The most promising compound 15c, with an IC50 (FXa) value of 0.14μM and 98% inhibition rate, warranted further investigation as an FXa inhibitor.

Keywords: Anticoagulant activity; FXa; Synthesis; Tetrahydropyrazolopyridone derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticoagulants / chemical synthesis*
  • Anticoagulants / pharmacology
  • Anticoagulants / therapeutic use
  • Binding Sites
  • Blood Coagulation / drug effects
  • Catalytic Domain
  • Drug Design*
  • Factor Xa / chemistry*
  • Factor Xa / metabolism
  • Factor Xa Inhibitors / chemical synthesis*
  • Factor Xa Inhibitors / pharmacology
  • Factor Xa Inhibitors / therapeutic use
  • Humans
  • Molecular Docking Simulation
  • Protein Binding
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Rabbits
  • Rats
  • Structure-Activity Relationship
  • Venous Thrombosis / drug therapy

Substances

  • Anticoagulants
  • Factor Xa Inhibitors
  • Pyrazoles
  • Pyridines
  • pyrazolopyridine
  • Factor Xa