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

Maxim Frizler; Friederike Lohr; Norbert Furtmann; Julia Kläs; Michael Gütschow

doi:10.1021/jm101272p

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

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

Authors

Maxim Frizler¹, Friederike Lohr, Norbert Furtmann, Julia Kläs, Michael Gütschow

Affiliation

¹ Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.

PMID: 21128614
DOI: 10.1021/jm101272p

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Aza Compounds
Dipeptides
Nitriles
Cathepsin K