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More MS news articles for April 2004

Khellinone derivatives as blockers of the voltage-gated potassium channel Kv1.3: synthesis and immunosuppressive activity

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15084131

J Med Chem. 2004 Apr 22;47(9):2326-36
Baell JB, Gable RW, Harvey AJ, Toovey N, Herzog T, Hansel W, Wulff H.
The Walter and Eliza Hall Institute of Medical Research Biotechnology Centre, 4 Research Avenue, La Trobe R&D Park, Bundoora 3086, Australia

The voltage-gated potassium channel Kv1.3 constitutes a promising new target for the treatment of T-cell-mediated autoimmune diseases such as multiple sclerosis.

In this study, we report the discovery of two new classes of Kv1.3 blockers based on the naturally occurring compound khellinone, 5-acetyl-4,7-dimethoxy-6-hydroxybenzofuran: (1) khellinone dimers linked via the alkylation of the 6-hydroxy groups and (2) chalcone derivatives of khellinone formed by Claisen-Schmidt condensation of the 5-acetyl group with aryl aldehydes.

In particular, the chalcone 3-(4,7-dimethoxy-6-hydroxybenzofuran-5-yl)-1-phenyl-3-oxopropene (16) and several of its derivatives inhibited Kv1.3 with K(d) values of 300-800 nM and a Hill coefficient of 2, displayed moderate selectivity over other Kv1-family K(+) channels, suppressed T-lymphocyte proliferation at submicromolar concentrations, and showed no signs of acute toxicity in mice.

Because of their relatively low molecular weight and lipophilicity and their high affinity to Kv1.3, aryl-substituted khellinone derivatives represent attractive lead compounds for the development of more potent and selective Kv1.3 blocking immunosuppressants.