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Primary amides as selective inhibitors of cathepsin K. 2007
Serge Léger, and
Christopher I Bayly, and
W Cameron Black, and
Sylvie Desmarais, and
Jean-Pierre Falgueyret, and
Frédéric Massé, and
M David Percival, and
Jean-François Truchon
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Que., Canada H9R 4P8. leger@merck.com
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.
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