Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K

Bioorg Med Chem Lett. 2005 Nov 1;15(21):4741-4. doi: 10.1016/j.bmcl.2005.07.071.

Abstract

The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The non-basic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compounds are 10- to 20-fold more potent than the corresponding amide derivatives. Compound 8 is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.

MeSH terms

  • Amides / chemistry
  • Cathepsin K
  • Cathepsins / antagonists & inhibitors*
  • Dipeptides / chemical synthesis
  • Dipeptides / pharmacology
  • Ethylamines / chemical synthesis
  • Ethylamines / pharmacology*
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Amides
  • Dipeptides
  • Ethylamines
  • Protease Inhibitors
  • trifluoroethylamine
  • Cathepsins
  • CTSK protein, human
  • Cathepsin K