Cathepsin S (CatS) is a cysteine protease involved in the antigen presentation process and in extra cellular matrix degradation. Dysregulated CatS activity is a driver for chronic inflammation, destructive proteolysis, arterial calcification and increased neoangiogenesis. Therefore CatS is an interesting target for several indications such as autoimmune diseases, cancer or cardio vascular diseases. One approach to inhibit the proteolytic activity of CatS is to block its active site with covalent reversible inhibitors which react with the cysteine present in the catalytic triad. This presentation will focus on the identification and optimization of covalent reversible CatS inhibitors via X-ray structure elucidation and molecular modeling to improve potency, selectivity, reversibility, and ADME properties.

Discovery of highly potent and selective covalent reversible cathepsin S inhibitors

245th National Meeting (2013)

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