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 α 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.