Dipeptide nitrile inhibitors of cathepsin K

Bioorg Med Chem Lett. 2006 May 1;16(9):2549-54. doi: 10.1016/j.bmcl.2006.01.104. Epub 2006 Feb 9.

Abstract

A series of dipeptidyl nitriles as inhibitors of cathepsin K have been explored starting from lead structure 1 (Cbz-Leu-NH-CH2-CN, IC50 = 39 nM). Attachment of non-natural amino acid side chains in P1 and modification of the P3 subunit led to inhibitors with higher potency and improved pharmacokinetic properties.

MeSH terms

  • Animals
  • Cathepsin K
  • Cathepsins / antagonists & inhibitors*
  • Cathepsins / metabolism
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry
  • Dipeptides / pharmacology*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • In Vitro Techniques
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Nitriles / chemical synthesis
  • Nitriles / chemistry
  • Nitriles / pharmacology*
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Dipeptides
  • Enzyme Inhibitors
  • Nitriles
  • Cathepsins
  • CTSK protein, human
  • Cathepsin K
  • Ctsk protein, rat