Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 17, Issue 15, Pages 4328-4332Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2007.05.024
Keywords
cathepsin inhibitor; primary amide; selective; substrate
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The nitrile warhead used in a series of cathepsin K inhibitors can be replaced by a less electrophilic primary arnide. 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 IC50 of 10 nM against cathepsin K and excellent selectivity versus the other cathepsins. (c) 2007 Published by Elsevier Ltd.
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