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

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• 作者：Jure Bori拧ek ; Matej Vizovi拧ek ; Piotr Sosnowski ; Boris Turk ; Du拧an Turk ; Barbara Mohar ; Marjana Novi膷
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 10, 2015
• 年：2015
• 卷：58
• 期：17
• 页码：6928-6937
• 全文大小：507K
• ISSN：1520-4804

文摘

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鈥?0 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.