Dipeptide nitrile inhibitors of cathepsin K

A series of dipeptidyl nitriles as inhibitors of cathepsin K have been explored starting from lead structure 1 (Cbz–Leu–NH–CH2–CN, IC50 = 39 nM). Attachment of non-natural amino acid side chains in P1 and modification of the P3 subunit led to inhibitors with higher potency and improved pharmacokinetic properties.

Graphical abstractA series of dipeptidyl nitriles as inhibitors of cathepsin K have been explored starting from lead structure 1 (Cbz–Leu–NH–CH2–CN, IC50 = 39 nM). Attachment of non-natural amino acid side chains in P1 and modification of the P3 subunit led to inhibitors with higher potency and improved pharmacokinetic properties.Figure optionsDownload full-size imageDownload as PowerPoint slide