1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides as Potent Factor Xa Inhibitors. Part 3: Design, Synthesis and SAR of Orally Bioavailable benzamidine-P4 Inhibitors

Bioorg Med Chem Lett. 2004 Mar 8;14(5):1229-34. doi: 10.1016/j.bmcl.2003.12.054.

Abstract

Using N,N-dialkylated benzamidines as the novel P4 motifs, we have designed and synthesized a class of 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent and selective fXa inhibitors with significantly improved hydrophilicity and in vitro anticoagulant activity. These benzamidine-P4 fXa inhibitors have displayed excellent oral bioavailability and long half-life.

MeSH terms

  • Administration, Oral
  • Amides / administration & dosage
  • Amides / chemical synthesis*
  • Amides / metabolism
  • Animals
  • Antithrombin III / administration & dosage
  • Antithrombin III / chemical synthesis*
  • Antithrombin III / metabolism
  • Benzamidines / antagonists & inhibitors*
  • Benzamidines / metabolism
  • Biological Availability
  • Drug Design
  • Humans
  • Pyrazoles / administration & dosage
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Amides
  • Benzamidines
  • Pyrazoles
  • pyrazole
  • Antithrombin III