title: Primary amides as selective inhibitors of cathepsin K.
abstract: The nitrile warhead used in a series of cathepsin K inhibitors can be replaced by a less electrophilic primary amide. The accompanying loss of potency can be partially recovered by introducing a substituent alpha to the amide. The potency gain resulting from this addition is not achieved with the nitrile derivatives due to a different geometry of the cysteine adduct in the enzyme active site. This study led to the identification of the primary amide 2g, which is an inhibitory substrate, with an IC(50) of 10 nM against cathepsin K and excellent selectivity versus the other cathepsins.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Que., Canada H9R 4P8. leger@merck.com
authors.forename: Serge
authors.initials: S
authors.lastname: Léger
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Bayly
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
authors.forename: Sylvie
authors.initials: S
authors.lastname: Desmarais
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: Frédéric
authors.initials: F
authors.lastname: Massé
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Truchon
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D013237:Stereoisomerism
chemical_list: D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; D056657:Cathepsin K