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J Med Chem. 2011 Jan 13;54(1):396-400. doi: 10.1021/jm101272p. Epub 2010 Dec 3.

Structural optimization of azadipeptide nitriles strongly increases association rates and allows the development of selective cathepsin inhibitors.

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Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.

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  • J Med Chem. 2011 Jan 13;54(1):399.


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.

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