Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2622-2628. doi: 10.1016/j.bmcl.2017.03.002. Epub 2017 Mar 6.

Abstract

Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.

Keywords: Aminobenzisoxazole; Anticoagulant; Azabicyclic ring; Factor IXa inhibitor; Structure based drug design.

MeSH terms

  • Animals
  • Binding Sites
  • Blood Coagulation / drug effects
  • Crystallography, X-Ray
  • Dogs
  • Drug Design
  • Drug Evaluation, Preclinical
  • Factor IXa / antagonists & inhibitors*
  • Factor IXa / metabolism
  • Half-Life
  • Humans
  • Inhibitory Concentration 50
  • Isoxazoles / chemistry*
  • Isoxazoles / metabolism
  • Isoxazoles / pharmacology
  • Molecular Dynamics Simulation
  • Partial Thromboplastin Time
  • Protein Structure, Tertiary
  • Prothrombin Time
  • Rats
  • Structure-Activity Relationship

Substances

  • Isoxazoles
  • Factor IXa