Design, synthesis and biological evaluation of anthranilamide derivatives as potential factor Xa (fXa) inhibitors

Bioorg Med Chem. 2018 Dec 15;26(23-24):5987-5999. doi: 10.1016/j.bmc.2018.09.012. Epub 2018 Sep 11.

Abstract

Factor Xa (fXa) is a crucial player in various thromboembolic disorders. Inhibition of fXa can provide safe and effective antithrombotic effects. In this study, a series of anthranilamide compounds were designed by utilizing structure-based design strategies. Optimization at P1 and P4 groups led to the discovery of compound 16g: a highly potent, selective fXa inhibitor with pronounced in vitro anticoagulant activity. Moreover, 16g also displayed excellent in vivo antithrombotic activity in the rat venous thrombosis (VT) and arteriovenous shunt (AV-SHUNT) models. The bleeding risk evaluation showed that 16g had a safer profile than that of betrixaban at 1 mg/kg and 5 mg/kg dose. Additionally, 16g also exhibited satisfactory PK profiles. Eventually, 16g was selected to investigate its effect on hypoxia-reoxygenation- induced H9C2 cell viability. MTT results showed that H9C2 cell viability can be remarkably alleviated by 16g.

Keywords: Arteriovenous shunt; Bleeding risk; Factor Xa; H9C2 cell; Venous thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticoagulants / chemical synthesis
  • Anticoagulants / chemistry
  • Anticoagulants / pharmacology*
  • Arteriovenous Shunt, Surgical
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Factor Xa / metabolism*
  • Molecular Docking Simulation
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship
  • Venous Thrombosis / drug therapy*
  • Venous Thrombosis / metabolism
  • ortho-Aminobenzoates / chemical synthesis
  • ortho-Aminobenzoates / chemistry
  • ortho-Aminobenzoates / pharmacology*

Substances

  • Anticoagulants
  • ortho-Aminobenzoates
  • Factor Xa
  • anthranilamide