Novel route to the synthesis of peptides containing 2-amino-1′-hydroxymethyl ketones and their application as cathepsin K inhibitors

Cathepsin K is highly expressed in human osteoclasts, and is implicated in bone resorption. This makes it an attractive target for the treatment of osteoporosis. Peptides containing 2-amino-1′-hydroxymethyl ketones and 2-amino-1′-alkoxymethyl ketones were discovered as potent inhibitors of cathepsin K. A novel synthetic route was devised to facilitate rapid elucidation of the SAR of these inhibitors. The synthesis and SAR of hydroxymethyl ketones are presented.