The discovery of (2R,4R)-N-(4-chlorophenyl)-N- (2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (PD 0348292), an orally efficacious factor Xa inhibitor

Chem Biol Drug Des. 2007 Aug;70(2):100-12. doi: 10.1111/j.1747-0285.2007.00539.x.

Abstract

Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.

MeSH terms

  • Animals
  • Anticoagulants / chemical synthesis
  • Anticoagulants / pharmacokinetics
  • Anticoagulants / pharmacology
  • Antithrombin III / chemical synthesis*
  • Antithrombin III / pharmacokinetics
  • Antithrombin III / pharmacology*
  • Crystallography, X-Ray
  • Dogs
  • Humans
  • Male
  • Pyridones / chemical synthesis*
  • Pyridones / pharmacokinetics
  • Pyridones / pharmacology*
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / pharmacokinetics
  • Pyrrolidines / pharmacology*
  • Rabbits
  • Rats
  • Structure-Activity Relationship

Substances

  • Anticoagulants
  • N-(4-chlorophenyl)-N-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidiine-1,2-dicarboxamide
  • Pyridones
  • Pyrrolidines
  • Antithrombin III

Associated data

  • PDB/2PHB