Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L and their inhibitory effect on bone resorption

J Med Chem. 1998 Oct 22;41(22):4301-8. doi: 10.1021/jm9803065.

Abstract

Cathepsin L, a lysosomal cysteine protease, is secreted by osteoclasts and participates in bone collagen degradation. In a search for cathepsin L inhibitors as antiosteoporotic agents, a series of peptide aldehyde derivatives were prepared by two synthetic approaches, DMSO oxidation of the corresponding alcohol derivatives and DIBAL-H reduction of the corresponding N, O-dimethylhydroxylamide derivatives, and evaluated for inhibitory activity against human cathepsin L and for inhibitory effects on bone resorption. Some of the peptide aldehyde derivatives including alpha-acylamino aldehyde derivatives showed potent activities. Among these compounds, N-(1-naphthalenylsulfonyl-L-isoleucyl-L-tryptophanal (12) was selected as a candidate for further investigation. Compound 12, a potent, selective, and reversible inhibitor of human cathepsin L with an IC50 of 1.9 nM, inhibited the release of Ca2+ and hydroxyproline from bone in in vitro bone culture system and also prevented bone loss in ovariectomized mice at an oral dose of 50 mg/kg.

MeSH terms

  • Aldehydes / chemical synthesis*
  • Aldehydes / chemistry
  • Aldehydes / pharmacology
  • Animals
  • Bone Resorption / drug therapy*
  • Bone and Bones / drug effects
  • Bone and Bones / metabolism
  • Calcium / metabolism
  • Cathepsin L
  • Cathepsins / antagonists & inhibitors*
  • Cysteine Endopeptidases
  • Cysteine Proteinase Inhibitors / chemical synthesis*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Dipeptides / pharmacology
  • Endopeptidases*
  • Female
  • Humans
  • Hydroxyproline / metabolism
  • Mice
  • Mice, Inbred C3H
  • Naphthalenesulfonates / chemical synthesis*
  • Naphthalenesulfonates / chemistry
  • Naphthalenesulfonates / pharmacology
  • Organ Culture Techniques
  • Ovariectomy
  • Peptides / chemical synthesis*
  • Peptides / chemistry
  • Peptides / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / antagonists & inhibitors
  • Skull / drug effects
  • Skull / metabolism
  • Structure-Activity Relationship

Substances

  • Aldehydes
  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • N-(1-naphthalenylsulfonyl)isoleucyl-tryptophanal
  • Naphthalenesulfonates
  • Peptides
  • Recombinant Proteins
  • Cathepsins
  • Endopeptidases
  • Cysteine Endopeptidases
  • CTSL protein, human
  • Cathepsin L
  • Ctsl protein, mouse
  • Ctsl protein, rat
  • Hydroxyproline
  • Calcium