Primary amides as selective inhibitors of cathepsin K.
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.
Léger
Serge
S
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Que., Canada H9R 4P8. leger@merck.com
Bayly
Christopher I
CI
Black
W Cameron
WC
Desmarais
Sylvie
S
Falgueyret
Jean-Pierre
JP
Massé
Frédéric
F
Percival
M David
MD
Truchon
Jean-François
JF
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
D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; D056657:Cathepsin K