The design and synthesis of 20 thiosemicarbazones containing P1 arginine, lysine, ornithine, citrullene, and leucine sidechains as inhibitors as cathepsin B and cathepsin K based on SAR data has been accomplished.  A library of 20 of these C-terminal aldehyde thiosemicarbazones with variations in the P2 and P3 positions are described. Several of these compounds have proven to be very potent inhibitors of human cathepsin B and K activity as measured using either spectrophotometric (BANA) or fluorometric assay (Cbz-Phe-Arg-AMC) techniques. The thiosemicarbazones showed mixed and non-competitive inhibition. Compounds showing the weakest inhibition of cathepsin B activity and the strongest inhibition of cathepsin K activity (IC50 values range from 1.2 to 2.4 nM) were those that contain a C-terminal leucine aldehyde or thiosemicarbazone with either a citrullene or glutamine in the P3 position.

New cathepsin B and K inhibitors utilizing thiosemicarbazones

245th National Meeting (2013)

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