Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor

Bioorg Med Chem Lett. 2009 Apr 15;19(8):2179-85. doi: 10.1016/j.bmcl.2009.02.111. Epub 2009 Mar 3.

Abstract

Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Anticoagulants / administration & dosage
  • Anticoagulants / chemical synthesis*
  • Anticoagulants / pharmacology*
  • Benzamides / administration & dosage
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacology*
  • Catalytic Domain / drug effects
  • Cell Line
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery / methods*
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / genetics
  • Factor Xa / metabolism
  • Factor Xa Inhibitors*
  • Humans
  • Macaca fascicularis
  • Pyridines / administration & dosage
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology*
  • Rabbits
  • Rats

Substances

  • Anticoagulants
  • Benzamides
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Factor Xa Inhibitors
  • KCNH2 protein, human
  • Pyridines
  • betrixaban
  • Factor Xa