title: Exploration of the P2-P3 SAR of aldehyde cathepsin K inhibitors.
abstract: The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S2 and S3 subsites with a series of carbamate derivatized norleucine aldehydes substituted at the P2 and P3 positions afforded analogs with cathepsin K IC50s between 600 nM and 130 pM.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Boros
authors.forename: David N
authors.initials: DN
authors.lastname: Deaton
authors.forename: Anne M
authors.initials: AM
authors.lastname: Hassell
authors.forename: Robert B
authors.initials: RB
authors.lastname: McFadyen
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Miller
authors.forename: Larry R
authors.initials: LR
authors.lastname: Miller
authors.forename: Margot G
authors.initials: MG
authors.lastname: Paulick
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shewchuk
authors.forename: James B
authors.initials: JB
authors.lastname: Thompson
authors.forename: Derril H
authors.initials: DH
authors.lastname: Willard
authors.forename: Lois L
authors.initials: LL
authors.lastname: Wright
mesh_terms: D000447:Aldehydes / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D002219:Carbamates / Q000737:chemistry; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D009646:Norleucine / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000447:Aldehydes; D002219:Carbamates; D011480:Protease Inhibitors; D009646:Norleucine; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K