MEDI 214 |
| Cathepsin S (CatS) is a lysosomal cysteine protease which has been shown to be critical in antigen presentation by the major histocompatibility class II complex (MHC II). Selective inhibition of CatS has been suggested as a potential therapeutic approach for the regulation of immune hyperresponsiveness, such as rheumatoid arthritis, multiple sclerosis, asthma and allergy. At GNF, we discovered a series of arylaminoethyl amides as noncovalent inhibitors of cathepsin S by HTS. Pharmacokinetic liabilities that often hinder the development of compounds against protease targets were addressed by the use of amino acid mimetics, such as succinic acids. Several novel noncovalent cathepsin S inhibitors were identified to possess high cathepsin S affinity (Ki < 10 nM) and excellent selectivity (>100 fold) over cathespins K, L and B. Molecular modeling, structure based drug design, synthesis and in vitro activity will be described. |
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General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster
Sci-Mix
Division of Medicinal Chemistry |