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
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Aldehydes / chemical synthesis*
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Aldehydes / chemistry
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Aldehydes / pharmacology
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Animals
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Bone Resorption / drug therapy*
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Bone and Bones / drug effects
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Bone and Bones / metabolism
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Calcium / metabolism
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Cathepsin L
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Cathepsins / antagonists & inhibitors*
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Cysteine Endopeptidases
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Cysteine Proteinase Inhibitors / chemical synthesis*
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Cysteine Proteinase Inhibitors / chemistry
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Cysteine Proteinase Inhibitors / pharmacology
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Dipeptides / chemical synthesis*
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Dipeptides / chemistry
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Dipeptides / pharmacology
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Endopeptidases*
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Female
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Humans
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Hydroxyproline / metabolism
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Mice
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Mice, Inbred C3H
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Naphthalenesulfonates / chemical synthesis*
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Naphthalenesulfonates / chemistry
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Naphthalenesulfonates / pharmacology
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Organ Culture Techniques
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Ovariectomy
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Peptides / chemical synthesis*
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Peptides / chemistry
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Peptides / pharmacology
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Rats
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Rats, Sprague-Dawley
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Recombinant Proteins / antagonists & inhibitors
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Skull / drug effects
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Skull / metabolism
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Structure-Activity Relationship
Substances
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Aldehydes
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Cysteine Proteinase Inhibitors
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Dipeptides
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N-(1-naphthalenylsulfonyl)isoleucyl-tryptophanal
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Naphthalenesulfonates
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Peptides
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Recombinant Proteins
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Cathepsins
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Endopeptidases
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Cysteine Endopeptidases
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CTSL protein, human
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Cathepsin L
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Ctsl protein, mouse
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Ctsl protein, rat
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Hydroxyproline
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Calcium