title: Potent dipeptidylketone inhibitors of the cysteine protease cathepsin K.
abstract: Cathepsin K (EC 3.4.22.38) is a cysteine protease of the papain superfamily which is selectively expressed within the osteoclast. Several lines of evidence have pointed to the fact that this protease may play an important role in the degradation of the bone matrix. Potent and selective inhibitors of cathepsin K could be important therapeutic agents for the control of excessive bone resorption. Recently a series of peptide aldehydes have been shown to be potent inhibitors of cathepsin K. In an effort to design more selective and metabolically stable inhibitors of cathepsin K, a series of electronically attenuated alkoxymethylketones and thiomethylketones inhibitors have been synthesized. The X-ray co-crystal structure of one of these analogues in complex with cathepsin K shows the inhibitor binding in the primed side of the enzyme active site with a covalent interaction between the active site cysteine 25 and the carbonyl carbon of the inhibitor.
authors.affiliation: Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA. robert_w_marquis@sbphrd.com
authors.forename: R W
authors.initials: RW
authors.lastname: Marquis
authors.forename: Y
authors.initials: Y
authors.lastname: Ru
authors.forename: D S
authors.initials: DS
authors.lastname: Yamashita
authors.forename: H J
authors.initials: HJ
authors.lastname: Oh
authors.forename: J
authors.initials: J
authors.lastname: Yen
authors.forename: S K
authors.initials: SK
authors.lastname: Thompson
authors.forename: T J
authors.initials: TJ
authors.lastname: Carr
authors.forename: M A
authors.initials: MA
authors.lastname: Levy
authors.forename: T A
authors.initials: TA
authors.lastname: Tomaszek
authors.forename: C F
authors.initials: CF
authors.lastname: Ijames
authors.forename: W W
authors.initials: WW
authors.lastname: Smith
authors.forename: B
authors.initials: B
authors.lastname: Zhao
authors.forename: C A
authors.initials: CA
authors.lastname: Janson
authors.forename: S S
authors.initials: SS
authors.lastname: Abdel-Meguid
authors.forename: K J
authors.initials: KJ
authors.lastname: D'Alessio
authors.forename: M S
authors.initials: MS
authors.lastname: McQueney
authors.forename: D F
authors.initials: DF
authors.lastname: Veber
mesh_terms: D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis*; D010450:Endopeptidases; D007659:Ketones / Q000737:chemistry*; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007659:Ketones; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; D056668:Cathepsin L; D056657:Cathepsin K