Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 17, Issue 4, Pages 998-1002Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2006.11.044
Keywords
cathepsin K; nitrile; osteoporosis; cyanamide; amino-acetonitrile; nitrile warhead; irreversible covalent binding; cysteine adduct; calculated electrophilicity
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Nitrile-based inhibitors of cathepsin K have been known for some time and mechanism-of-action studies have demonstrated that cysteinyl proteases interact with nitriles in a reversible fashion. Three main classes of nitrile-containing inhibitors have been published in the cathepsin K field: (i) cyanamides, (ii) aromatic nitriles, and (iii) aminoacetonitriles. A computational approach was used to calculate the theoretical reactivities of diverse nitriles and this was found to correlate with their extent of reactivity with free cysteine. Moreover, there is a tentative link between high reactivity with cysteine and the potential to lead to irreversible covalent binding to proteins. (c) 2006 Elsevier Ltd. All rights reserved.
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