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

Autor:	Friederike Lohr, Michael Gütschow, Julia Kläs, Norbert Furtmann, Maxim Frizler
Rok vydání:	2010
Předmět:	Cathepsin Aza Compounds Nitrile Chemistry Stereochemistry Cathepsin K Dipeptides Methylation Kinetics Structure-Activity Relationship chemistry.chemical_compound Amide Nitriles Drug Discovery Molecular Medicine Structure–activity relationship Selectivity Linker
Zdroj:	Journal of Medicinal Chemistry. 54:396-400
ISSN:	1520-4804 0022-2623
DOI:	10.1021/jm101272p
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cad50669953396b29e66ee2fe8a45aae https://doi.org/10.1021/jm101272p Zobrazit plný text záznamu