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

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journal contribution
posted on 10.09.2015, 00:00 by Jure Borišek, Matej Vizovišek, Piotr Sosnowski, Boris Turk, Dušan Turk, Barbara Mohar, Marjana Novič
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 Ki 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.