Khellinone Derivatives as Blockers of the Voltage-Gated Potassium Channel Kv1.3: Synthesis and Immunosuppressive Activity

Jonathan B. Baell, Robert W. Gable, Andrew J. Harvey, Nathan Toovey, Tanja Herzog, Wolfram Hänsel, Heike Wulff

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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 Kd 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.

Original languageEnglish
Pages (from-to)2326-2336
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number9
Publication statusPublished - 22 Apr 2004
Externally publishedYes

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