Tuesday, 24 May 2005 - 2:05 PM

This presentation is part of: Proteinase

The Discovery and Development of Non-Covalent Cathepsin S Inhibitors

James P. Edwards, Johnson & Johnson Pharmaceutical Research and Development, San Diego, CA

The cysteine protease cathepsin S (CatS) has received much recent attention as a target for therapeutic intervention in a range of diseases of the immune system. CatS is expressed mainly in antigen-presenting cells and has been implicated in the presentation of antigens to CD4+ T-cells through the use of both knock-out animals and systemic administration of a peptidic, irreversible cysteine protease inhibitor, LHVS. The CatS inhibitors reported to date rely on covalent attachment of an electrophilic peptide-derived ligand to the active site thiol to achieve potent enzyme inhibition. In this presentation, the discovery, SAR investigations, and development of the first non-peptidic, non-covalent inhibitors of cathepsin S are described. Directed and high-through-put screening generated a set of CatS hits from which two lead structures were identified as promising starting points for a drug discovery effort. Lead optimization afforded potent (IC50 < 10 nM) and selective inhibitors of CatS demonstrating excellent cellular activity and good oral bioavailability and safety in pre-clinical species. The issues specific to this program that needed to be overcome to identify the clinical candidates will be discussed in detail.

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