Novel route to the synthesis of peptides containing 2-amino-1'-hydroxymethyl ketones and their application as cathepsin K inhibitors

Bioorg Med Chem Lett. 2002 Oct 21;12(20):2887-91. doi: 10.1016/s0960-894x(02)00611-x.

Abstract

Cathepsin K is highly expressed in human osteoclasts, and is implicated in bone resorption. This makes it an attractive target for the treatment of osteoporosis. Peptides containing 2-amino-1'-hydroxymethyl ketones and 2-amino-1'-alkoxymethyl ketones were discovered as potent inhibitors of cathepsin K. A novel synthetic route was devised to facilitate rapid elucidation of the SAR of these inhibitors. The synthesis and SAR of hydroxymethyl ketones are presented.

MeSH terms

  • Cathepsin K
  • Cathepsins / antagonists & inhibitors*
  • Drug Design
  • Humans
  • Indicators and Reagents
  • Ketones / chemical synthesis*
  • Ketones / pharmacology*
  • Osteoclasts / drug effects
  • Osteoclasts / enzymology
  • Osteoporosis / drug therapy
  • Peptides / chemical synthesis*
  • Peptides / pharmacology*
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Indicators and Reagents
  • Ketones
  • Peptides
  • Protease Inhibitors
  • Cathepsins
  • CTSK protein, human
  • Cathepsin K