Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors

The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.

Graphical abstractBy using a small atom (Cl, F, or Me) to increase the torsion angle between the phenyl ring and the attached secondary amide, trifluoromethylphenyl motif was applied successfully as P2 for aldehyde/ketoamide-based cathepsin S inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide