Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?

Bioorg Med Chem Lett. 2006 Feb 15;16(4):978-83. doi: 10.1016/j.bmcl.2005.10.108. Epub 2005 Nov 15.

Abstract

Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.

MeSH terms

  • Aldehydes / chemistry*
  • Animals
  • Cathepsin K
  • Cathepsins / antagonists & inhibitors*
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydrogen-Ion Concentration
  • Hydrolysis
  • Models, Molecular
  • Molecular Conformation
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacology
  • Rats
  • Semicarbazones / chemical synthesis
  • Semicarbazones / chemistry
  • Semicarbazones / pharmacology*
  • Solubility
  • Structure-Activity Relationship

Substances

  • Aldehydes
  • Enzyme Inhibitors
  • Prodrugs
  • Semicarbazones
  • Cathepsins
  • CTSK protein, human
  • Cathepsin K
  • Ctsk protein, rat