Structural Optimization of Azadipeptide Nitriles Strongly Increases Association Rates and Allows the Development of Selective Cathepsin Inhibitors

Using the example of cathepsin K, we demonstrate the design of highly potent and selective azadipeptide nitrile inhibitors. A systematic scan with respect to P2 and P3 substituents was carried out. Structural modifications strongly affected the enzyme−inhibitor association (but not dissociation) rat...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2011-01, Vol.54 (1), p.396-400
Main Authors: Frizler, Maxim, Lohr, Friederike, Furtmann, Norbert, Kläs, Julia, Gütschow, Michael
Format: Article
Language:English
Subjects:
Aza Compounds - chemical synthesis
Aza Compounds - chemistry
Cathepsin K - antagonists & inhibitors
Cathepsin K - chemistry
Dipeptides - chemical synthesis
Dipeptides - chemistry
Kinetics
Nitriles - chemical synthesis
Nitriles - chemistry
Structure-Activity Relationship
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Summary:Using the example of cathepsin K, we demonstrate the design of highly potent and selective azadipeptide nitrile inhibitors. A systematic scan with respect to P2 and P3 substituents was carried out. Structural modifications strongly affected the enzyme−inhibitor association (but not dissociation) rate. A combination of optimized P2 and P3 substituents with a methylation of the P3−P2 amide linker resulted in the picomolar cathepsin K inhibitor 19 with remarkable selectivity over cathepsins L, B, and S.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm101272p