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Updated: Jun 6, 2026

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions
Published on: July 28, 2022
Structural optimization of azadipeptide nitriles strongly increases association rates and allows the development of
Maxim Frizler1, Friederike Lohr, Norbert Furtmann
1Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
Abstract:
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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