Khellinone derivatives as blockers of the voltage-gated potassium channel Kv1.3: Synthesis and immunosuppressive activity
Publication Year 2004-04-22, Volume 47, Issue #9, Page 2326-2336
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- Publication Type
- Journal Article
- 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-hydroxybeiizofuran: (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.
- AMER CHEMICAL SOC
- EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; T-CELL ACTIVATION; K+ CHANNELS; CHALCONE DERIVATIVES; INHIBITORY PROPERTIES; MULTIPLE-SCLEROSIS; NERVE-FIBERS; POTENT; CORREOLIDE; DISORDERS
- Publisher's Version
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Creation Date: 2004-04-22 12:00:00Last Modified: 0001-01-01 12:00:00