Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K

The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The non-basic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compounds are 10- to 20-fold more potent than the corresponding amide derivatives. Compound 8 is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.

Graphical abstractReplacing an amide bond with a trifluoroethylamine leads to potent and selective inhibitors of cathepsin K. The CF3 group provides a non-basic amine that makes a good hydrogen bond with the enzyme active site.Figure optionsDownload full-size imageDownload as PowerPoint slide