Potent and selective ketoamide-based inhibitors of cysteine protease, cathepsin K

J Med Chem. 2004 Oct 7;47(21):5049-56. doi: 10.1021/jm0400799.


Cathepsin K, a lysosomal cysteine protease of the papain superfamily, is abundantly and selectively expressed in osteoclasts, suggesting that this enzyme is crucial for bone resorption. Prevention of osteoclast-mediated bone resorption via inhibition of cathepsin K could be an effective approach to prevent osteoporosis. Potent and selective reversible ketoamide-based inhibitors have been identified in the present study. Using a known crystal structure of a ketoamide-based inhibitor, information from residues that form the P2/P3 pocket was used in the design of inhibitors that could allow for gains in selectivity and potency. Further, incorporation of P' selective heterocycles, along with the P2/P3 modifications, is also described. These modifications have resulted in potent and selective cathepsin K inhibitors that allow for improvements in their physiochemical properties and represent a viable lead series for the discovery of new therapies for the prevention and treatment of osteoporosis

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Carbamates / chemical synthesis
  • Carbamates / chemistry
  • Cathepsin K
  • Cathepsins / antagonists & inhibitors*
  • Cathepsins / chemistry
  • Cyclobutanes / chemical synthesis
  • Cyclobutanes / chemistry
  • Cyclopentanes / chemical synthesis
  • Cyclopentanes / chemistry
  • Ketones / chemical synthesis*
  • Ketones / chemistry
  • Models, Molecular
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Structure-Activity Relationship


  • Amides
  • Carbamates
  • Cyclobutanes
  • Cyclopentanes
  • Ketones
  • Pyrazoles
  • Cathepsins
  • Cathepsin K