title: Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1', P1, and/or P3 substitutions.
abstract: A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P(2) substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P(3), P(1), and P(1') moieties afforded orally bioavailable inhibitors.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Barrett
authors.forename: John G
authors.initials: JG
authors.lastname: Catalano
authors.forename: David N
authors.initials: DN
authors.lastname: Deaton
authors.forename: Anne M
authors.initials: AM
authors.lastname: Hassell
authors.forename: Stacey T
authors.initials: ST
authors.lastname: Long
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Miller
authors.forename: Larry R
authors.initials: LR
authors.lastname: Miller
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shewchuk
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wells-Knecht
authors.forename: Derril H
authors.initials: DH
authors.lastname: Willard
authors.forename: Lois L
authors.initials: LL
authors.lastname: Wright
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K