Sukanthini Thurairatnam

Potent small molecule inhibitors of spleen tyrosine kinase (Syk)

A series of oxindoles demonstrating inhibition of the phosphorylation of biotinylated substrates of Syk and IgE/Fc epsilon RI triggered basophil cell degranulation has been identified. A study of the SAR around sulfonamide 31 (IC(50)=5 nM, EC(50)=1400 nM) is discussed. The modest cellular activity representative of the sulfonamide series was overcome when the Polar Surface Area was lowered to <110 A(2), leading to the identification of amide 32 (IC(50)=145 nM, EC(50)=100 nM).

Mapping the kinase domain of Janus Kinase 3.

The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed.

Cathepsin S inhibitors

Cysteine proteases have attracted considerable interest over the past decade. Lysosomal cysteine protease cathepsin S plays an important role in antigen presentation and matrix degradation. Interest for this enzyme has recently grown and ~ 70 patents have appeared over the last 3 years, targeting cathepsin S either solely or among other related cysteine proteases. With the rapidly growing understanding of the pharmacology of cathepsin S, a number of pharmaceutical companies have reported to be actively seeking inhibitors to treat inflammatory and autoimmune diseases. The major players in this field are Aventis Pharmaceuticals in collaboration with Celera Genomics (previously Axys pharmaceuticals), Boehringer Ingelheim and Glaxo SmithKline. These companies report compounds undergoing preclinical evaluation. Most of the disclosed inhibitors contain an electrophilic warhead, such as nitriles, activated ketones, aldehydes and β-lactams, that interacts with the catalytic cysteine thiol.