Development of N‑(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors

• Published in: Journal of medicinal chemistry 2015-09, Vol.58 (17), p.6928-6937
• Main Authors: Borišek, Jure, Vizovišek, Matej, Sosnowski, Piotr, Turk, Boris, Turk, Dušan, Mohar, Barbara, Novič, Marjana
• Format: Article
• Language: English
• Subjects: Benzoates - chemical synthesis; Benzoates - chemistry; Benzoates - pharmacology; Cathepsin K - antagonists & inhibitors; Crystallography, X-Ray; Cycloleucine - chemistry; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacology; Glycine - chemistry; Humans; Kinetics; Models, Molecular; Molecular Docking Simulation; Nitriles - chemical synthesis; Nitriles - chemistry; Nitriles - pharmacology; Protein Binding; Quantitative Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00746

Cathepsin K is a major drug target for osteoporosis and related-bone disorders. Using a combination of virtual combinatorial chemistry, QSAR modeling, and molecular docking studies, a series of cathepsin K inhibitors based on N-(functionalized benzoyl)-homocycloleucyl-glycinonitrile scaffold was developed. In order to avoid previous problems of cathepsin K inhibitors associated with lysosomotropism of compounds with basic character that resulted in off-target effects, a weakly- to nonbasic moiety was incorporated into the P3 position. Compounds 5, 6, and 9 were highly selective for cathepsin K when compared with cathepsins L and S, with the K i values in the 10–30 nM range. The kinetic studies revealed that the new compounds exhibited reversible tight binding to cathepsin K, while the X-ray structural studies showed covalent and noncovalent binding between the nitrile group and the catalytic cysteine (Cys25) site.