Structure-based development of pyridoxal propionate derivatives as specific inhibitors of cathepsin K in vitro and in vivo

Biochem Biophys Res Commun. 2000 Jan 27;267(3):850-4. doi: 10.1006/bbrc.1999.1953.

Abstract

We found that pyridoxal phosphate shows considerable inhibition of cathepsins. CLIK-071, in which the phosphate ester of position 3 of pyridoxal phosphate was replaced by propionate, strongly inhibited cathepsin B. Three new types of synthetic pyridoxal propionate derivatives showing specific inhibition of cathepsin K were developed. New synthetic pyridoxal propionate derivatives, -162, -163, and -164, in which the methyl arm of position 6 of CLIK-071 was additionally modified, strongly inhibited cathepsin K and cathepsin S weakly, but other cathepsins were not inhibited. CLIK-166, in which the position 4 aldehyde of CLIK-071 is replaced by a vinyl radical and position 5 is additionally modified, showed cathepsin K-specific inhibition at 10(-5) M. Pit formation due to bone collagen degradation by cathepsin K of rat osteoclasts was specifically suppressed by administration of CLIK-164, but not by inhibitors of cathepsin L or B.

MeSH terms

  • Animals
  • Bone Resorption / prevention & control
  • Cathepsin B / antagonists & inhibitors
  • Cathepsin K
  • Cathepsins / antagonists & inhibitors*
  • Cysteine Proteinase Inhibitors / chemistry*
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Drug Design
  • Osteoclasts / enzymology
  • Pyridoxal / analogs & derivatives*
  • Pyridoxal / chemistry*
  • Pyridoxal / pharmacology*
  • Pyridoxal Phosphate / analogs & derivatives*
  • Pyridoxal Phosphate / chemistry
  • Pyridoxal Phosphate / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Cysteine Proteinase Inhibitors
  • Pyridoxal
  • Pyridoxal Phosphate
  • Cathepsins
  • Cathepsin B
  • Cathepsin K
  • Ctsk protein, rat