Orally bioavailable factor Xa inhibitors containing alpha-substituted gem-dimethyl P4 moieties

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3341-5. doi: 10.1016/j.bmcl.2014.05.101. Epub 2014 Jun 7.

Abstract

In an effort to identify a potential back-up to apixaban (Eliquis®), we explored a series of diversified P4 moieties. Several analogs with substituted gem-dimethyl moieties replacing the terminal lactam of apixaban were identified which demonstrated potent FXa binding affinity (FXa Ki), good human plasma anticoagulant activity (PT EC2x), cell permeability, and oral bioavailability.

Keywords: Factor Xa inhibitors; Thromboembolic disorders.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Cell Membrane Permeability / drug effects
  • Dogs
  • Dose-Response Relationship, Drug
  • Factor Xa / metabolism*
  • Factor Xa Inhibitors / administration & dosage
  • Factor Xa Inhibitors / chemistry
  • Factor Xa Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Pyrazoles / administration & dosage
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyridones / administration & dosage
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Structure-Activity Relationship

Substances

  • Factor Xa Inhibitors
  • Pyrazoles
  • Pyridones
  • apixaban
  • Factor Xa