Design, Synthesis, and Structure-Activity Relationship Study of Epoxysuccinyl-Peptide Derivatives as Cathepsin B Inhibitors.

Cathepsin B is a lysosomal cysteine protease involved in many diseases. The present research demonstrates that derivatives of epoxysuccinyl-peptide are effective and selective cathepsin B inhibitors. We synthesized a series of epoxysuccinyl-peptide derivatives based on the well-known cathepsin B inhibitor E64d. Specifically, we substituted the 2-methylpropane group at the R-1 position of E64d with a sulfane, such as ethyl(methyl) sulfane or benzyl(methyl) sulfane. We also designed and synthesized a library of molecules with various substituents at the R-2 position of E64d to replace 2-methylbutane. By studying the structure-activity relationships of these newly synthesized molecules as cathepsin B inhibitors, we demonstrated that substituting ethyl(methyl) sulfane for 2-methylbutane (R-2) of E64d improves the inhibitory activity and selectivity for cathepsin B inhibition. Our new cathepsin B inhibitors were highly effective and selective.