Synthesis of 3,4-diaminobenzoyl derivatives as factor Xa inhibitors

Eur J Med Chem. 2015 Aug 28:101:41-51. doi: 10.1016/j.ejmech.2015.06.012. Epub 2015 Jun 17.

Abstract

The coagulation factor Xa (FXa) plays a central role in the blood coagulation cascade. Recent studies have shown that FXa is a particularly attractive target for the development of oral antithrombotic agents. In view of the excellent pharmaceutical properties of 1,2-phenylenediamine-based FXa inhibitors and the reported structure-activity relationship (SAR) analysis of FXa inhibitors, we designed and synthesized a series of 3,4-diaminobenzoyl-based FXa inhibitors. Intensive SAR studies on this new series led to the discovery of 3,4-dimethoxyl substituted compound 7b. 7b is a highly potent, selective, direct FXa inhibitor with excellent in vivo antithrombotic activity.

Keywords: 3,4-Diaminobenzoyl-based FXa inhibitors; Antithrombotic agents; FXa inhibitor; Thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Factor Xa / metabolism*
  • Factor Xa Inhibitors / chemical synthesis*
  • Factor Xa Inhibitors / chemistry
  • Factor Xa Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Rabbits
  • Rats
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Factor Xa Inhibitors
  • N-(5-carbamoyl-2-(4-(2-oxopyridin-1(2H)-yl)benzamido)phenyl)-3,4-dimethoxybenzamide
  • Pyridones
  • Factor Xa