Design, synthesis and evaluation of isoxazolo[5,4-d]pyrimidin-4(5H)-one derivatives as antithrombotic agents

Bioorg Med Chem Lett. 2015 Feb 1;25(3):492-5. doi: 10.1016/j.bmcl.2014.12.039. Epub 2014 Dec 19.

Abstract

A series of isoxazolo[5,4-d]pyrimidin-4(5H)-one derivatives have been designed and synthesized as novel antithrombotic agents. The 4-acetoxyl substituted derivative (6g) displays very strong FXa inhibitory activity (IC50=0.013μM), excellent anticoagulant effect in human plasma (2×PT=2.12μM) and high selectivity to thrombin and trypsin. Docking investigation of 6g with FXa protein revealed that the pyrimidone ring of 6g formed a π-π interaction with the phenyl ring of Tyr99, and the carbonyl group in the P1 moiety formed multiple hydrogen bonds to Ser214 and Trp215. These results showed that isoxazolo[5,4-d]pyrimidin-4(5H)-one is an attractive scaffold for designing novel factor Xa inhibitors and 4-carbonyl substituted phenyl ring could be used as novel S1 binding element.

Keywords: Antithrombotic agent; Docking; Factor Xa; Isoxazolo[5,4-d]pyrimidin-4(5H)-one.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Drug Design*
  • Factor Xa / chemistry
  • Factor Xa / metabolism
  • Factor Xa Inhibitors / chemical synthesis
  • Factor Xa Inhibitors / chemistry
  • Factor Xa Inhibitors / metabolism
  • Fibrinolytic Agents / chemical synthesis*
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / metabolism
  • Humans
  • Molecular Docking Simulation
  • Oxazoles / chemical synthesis
  • Oxazoles / chemistry*
  • Oxazoles / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Pyridones / chemical synthesis
  • Pyridones / chemistry*
  • Pyridones / metabolism
  • Thrombin / antagonists & inhibitors*
  • Thrombin / metabolism
  • Trypsin / chemistry
  • Trypsin / metabolism

Substances

  • Factor Xa Inhibitors
  • Fibrinolytic Agents
  • Oxazoles
  • Pyridones
  • oxazolopyridinone
  • Trypsin
  • Thrombin
  • Factor Xa