title: Identification of a potent and selective non-basic cathepsin K inhibitor.
abstract: Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor. This compound showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The volumes of distribution close to unity were consistent with this compound not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Que., Canada H9R 4P8. chunsing_li@merck.com
authors.forename: Chun Sing
authors.initials: CS
authors.lastname: Li
authors.forename: Denis
authors.initials: D
authors.lastname: Deschenes
authors.forename: Sylvie
authors.initials: S
authors.lastname: Desmarais
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: Jacques Yves
authors.initials: JY
authors.lastname: Gauthier
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kimmel
authors.forename: Serge
authors.initials: S
authors.lastname: Léger
authors.forename: Frédéric
authors.initials: F
authors.lastname: Massé
authors.forename: Mary E
authors.initials: ME
authors.lastname: McGrath
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McKay
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Denis
authors.initials: D
authors.lastname: Riendeau
authors.forename: Sevgi B
authors.initials: SB
authors.lastname: Rodan
authors.forename: Michel
authors.initials: M
authors.lastname: Thérien
authors.forename: Vouy-Linh
authors.initials: VL
authors.lastname: Truong
authors.forename: Gregg
authors.initials: G
authors.lastname: Wesolowski
authors.forename: Robert
authors.initials: R
authors.lastname: Zamboni
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
mesh_terms: D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D008253:Macaca mulatta; D008958:Models, Molecular; D010052:Ovariectomy
chemical_list: D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; D056657:Cathepsin K