title: Benzodioxocin-3-ones and N-acyl-3-amino-3-buten-2-ones: novel classes of cathepsin K cysteine protease inhibitors.
abstract: The design, synthesis, enzymologic, and protein mass spectrometric characterization of benzodioxocin-3-one and N-acyl-3-amino-3-buten-2-one inhibitors of the cysteine protease cathepsin K are described. The benzodioxocin-3-one ring system is chemically unstable giving rise to a mixture of N-acyl-3-amino-3-buten-2-one and hemiketals. This mixture of N-acyl-3-amino-3-buten-2-one and hemiketals potently inhibits recombinant, human cathepsin K (IC50 = 36 nM) by a time-independent, irreversible mechanism. Formation of a covalent adduct between cathepsin K and inhibitor has been confirmed by mass spectrometry.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Collegeville, PA, USA. dennis.s.yamashita@gsk.com
authors.forename: D S
authors.initials: DS
authors.lastname: Yamashita
authors.forename: R
authors.initials: R
authors.lastname: Xie
authors.forename: H
authors.initials: H
authors.lastname: Lin
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: S D-H
authors.initials: SD
authors.lastname: Shi
authors.forename: C J
authors.initials: CJ
authors.lastname: Quinn
authors.forename: M E
authors.initials: ME
authors.lastname: Hemling
authors.forename: C
authors.initials: C
authors.lastname: Hissong
authors.forename: T A
authors.initials: TA
authors.lastname: Tomaszek
authors.forename: D F
authors.initials: DF
authors.lastname: Veber
mesh_terms: D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007659:Ketones; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534130:CTSK protein, human; D056657:Cathepsin K