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

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.
Authors	T Yasuma, S Oi, N Choh, T Nomura, N Furuyama, A Nishimura, Y Fujisawa, T Sohda
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 41 Issue 22 Pg. 4301-8 (Oct 22 1998) ISSN: 0022-2623 [Print] United States
PMID	9784105 (Publication Type: Journal Article)
Chemical References	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
Topics	Aldehydes (chemical synthesis, chemistry, pharmacology) Animals Bone Resorption (drug therapy) Bone and Bones (drug effects, metabolism) Calcium (metabolism) Cathepsin L Cathepsins (antagonists & inhibitors) Cysteine Endopeptidases Cysteine Proteinase Inhibitors (chemical synthesis, chemistry, pharmacology) Dipeptides (chemical synthesis, chemistry, pharmacology) Endopeptidases Female Humans Hydroxyproline (metabolism) Mice Mice, Inbred C3H Naphthalenesulfonates (chemical synthesis, chemistry, pharmacology) Organ Culture Techniques Ovariectomy Peptides (chemical synthesis, chemistry, pharmacology) Rats Rats, Sprague-Dawley Recombinant Proteins (antagonists & inhibitors) Skull (drug effects, metabolism) Structure-Activity Relationship

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