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

Article Details

Citation

Copy to clipboard

Baell JB, Gable RW, Harvey AJ, Toovey N, Herzog T, Hansel W, Wulff H

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

J Med Chem. 2004 Apr 22;47(9):2326-36.

PubMed ID

15084131 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Dalfampridine	Potassium voltage-gated channel subfamily A member 3	Kd (nM)	195000	N/A	N/A	Details