Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif

Bioorg Med Chem Lett. 2008 May 1;18(9):2865-70. doi: 10.1016/j.bmcl.2008.03.087. Epub 2008 Apr 8.

Abstract

2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (K(i)=1.2nM) that exhibits robust efficacy in canine anticoagulation and thrombosis models upon oral administration.

MeSH terms

  • Acetamides* / chemical synthesis
  • Acetamides* / pharmacokinetics
  • Acetamides* / therapeutic use
  • Administration, Oral
  • Amino Acid Motifs*
  • Animals
  • Anticoagulants / administration & dosage*
  • Anticoagulants / chemical synthesis
  • Anticoagulants / pharmacokinetics
  • Binding Sites
  • Disease Models, Animal
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Haplorhini
  • Humans
  • Hydrogen Bonding
  • Models, Chemical
  • Nitriles* / chemical synthesis
  • Nitriles* / pharmacokinetics
  • Nitriles* / therapeutic use
  • Rats
  • Structure-Activity Relationship
  • Thrombin / antagonists & inhibitors*
  • Thrombosis / drug therapy*

Substances

  • 2-cyano-6-fluorophenylacetamide
  • Acetamides
  • Anticoagulants
  • Nitriles
  • Thrombin