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

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.
Mesh Terms:
Animals, Benzofurans, Cell Division, Cell Line, Chalcone, Chalcones, Humans, Immunosuppressive Agents, Ion Channel Gating, Kv1.3 Potassium Channel, Mice, Molecular Structure, Potassium Channel Blockers, Potassium Channels, Potassium Channels, Voltage-Gated, Structure-Activity Relationship, T-Lymphocytes, Toxicity Tests, Acute
J Med Chem
Date: Apr. 22, 2004
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