Development of Nitrile-Based Peptidic Inhibitors of Cysteine Cathepsins

Author(s): Maxim Frizler, Marit Stirnberg, Mihiret Tekeste Sisay, Michael Gutschow

Journal Name: Current Topics in Medicinal Chemistry

Volume 10 , Issue 3 , 2010

Become EABM
Become Reviewer
Call for Editor


It is now becoming clear that several papain-like cysteine cathepsins are involved in the pathophysiology of diseases such as osteoporosis, autoimmune disorders, and cancer. Therefore, the development of potent and selective cathepsin inhibitors is an attractive subject for medicinal chemists. New advances have been made for nitrile-based inhibitors, leading to the identification of the cathepsin K inhibitor odanacatib and other candidates with potential for therapeutic use. This review summarizes the development of peptidic and peptidomimetic compounds with an electrophilic nitrile ‘warhead’ as inhibitors of the cysteine cathepsins B, S, L, C, and K. Peptide nitriles have been shown to reversibly react with the active site cysteine under formation of a covalent thioimidate adduct. The structural optimization with respect to the positions P3, P2, P1, P1, and P2 resulted in the identification of potent and selective inhibitors of the corresponding cathepsins. The underlying structure-activity relationships are discussed herein.

Keywords: Cathepsin, covalent modifier, cysteine protease, lysosomotropic property, osteoporosis, peptide nitrile, peptidomimetic, protease inhibitor, thioimidate

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2010
Page: [294 - 322]
Pages: 29
DOI: 10.2174/156802610790725452
Price: $65

Article Metrics

PDF: 63