title: Novel route to the synthesis of peptides containing 2-amino-1'-hydroxymethyl ketones and their application as cathepsin K inhibitors.
abstract: 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.
authors.affiliation: Celera, 180 Kimball Way, South San Francisco, CA 94080, USA. rohan.mendonca@celera.com
authors.forename: Rohan V
authors.initials: RV
authors.lastname: Mendonca
authors.forename: Shankar
authors.initials: S
authors.lastname: Venkatraman
authors.forename: James T
authors.initials: JT
authors.lastname: Palmer
mesh_terms: D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D007202:Indicators and Reagents; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology*; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology; D010024:Osteoporosis / Q000188:drug therapy; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007202:Indicators and Reagents; D007659:Ketones; D010455:Peptides; D011480:Protease Inhibitors; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K