Highly selective azadipeptide nitrile inhibitors for cathepsin K: design,synthesis and activity assayst

摘要

We have developed a series of azadipeptide nitriles with different P3 groups.A triaryl meta-phenyl derivative,compound 13,was not only a potent inhibitor for cathepsin K (Kt = 0.0031 nM),but also highly selective over both cathepsins B and S (~1000-fold).A protein-ligand docking study performed on the series provided a possible explanation why compound 13 could be significantly more potent than the others,especially compound 12 in the same series.