Highly selective aza-nitrile inhibitors for cathepsin K, structural optimization and molecular modeling.

As a new type of cathepsin K inhibitor, azadipeptide nitriles have the characteristics of proteolytic stability and excellent inhibitory activity, but they exhibit barely any satisfactory selectivity. Great efforts have focused on improving their selectivity toward cathepsin K. In this sequential study, we report the further structural optimization, synthesis, molecular modeling, and in vitro enzymatic assays of a new series of potent and selective inhibitors of cathepsin K without the P2-P3 amide linker. Significant selective improvements were achieved for cathepsin K over L, S and B, and a triaryl meta-product possessed the favorable balance between potency (Ki = 0.29 nM) and selectivity of cathepsin K over cathepsin L (320-fold), S (1784-fold) and B (8566-fold). We undertook a covalent protein-ligand docking study to explain the improved selectivity of several representative compounds. Such a selectivity improvement would be useful to avoid harmful side effects in practical applications of these compounds.