Synthesis of Peptide Aldehyde Derivatives as Selective Inhibitors of Human Cathepsin L and Their Inhibitory Effect on Bone Resorption.

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