A new class of blockers of the voltage-gated potassium channel Kv1.3 via modification of the 4- or 7-position of khellinone

Andrew J. Harvey, Jonathan B. Baell, Nathan Toovey, Daniel Homerick, Heike Wulff

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The voltage-gated potassium channel Kv1.3 constitutes an attractive target for the selective suppression of effector memory T cells in autoimmune diseases. We have previously reported the natural product khellinone, 1a, as a versatile lead molecule and identified two new classes of Kv1.3 blockers: (i) chalcone derivatives of khellinone, and (ii) khellinone dimers linked through the 6-position. Here we describe the multiple parallel synthesis of a new class of khellinone derivatives selectively alkylated at either the 4- or 7-position via the phenolic OH and show that several chloro, bromo, methoxy, and nitro substituted benzyl derivatives inhibit Kv1.3 with submicromolar potencies. Representative examples of the most potent compounds from each subclass, 11m (5-acetyl-4-(4′-chloro)benzyloxy-6-hydroxy-7-methoxybenzofuran) and 14m (5-acetyl-7-(4′-bromo)benzyloxy-6-hydroxy-4-methoxybenzofuran), block Kv1.3 with EC50 values of 480 and 400 nM, respectively. Both compounds exhibit moderate selectivity over other Kv1-family channels and HERG, are not cytotoxic, and suppress human T cell proliferation at low micromolar concentrations.

Original languageEnglish (US)
Pages (from-to)1433-1441
Number of pages9
JournalJournal of Medicinal Chemistry
Volume49
Issue number4
DOIs
StatePublished - Feb 23 2006

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Voltage-Gated Potassium Channels
T-cells
Derivatives
Chalcone
T-Lymphocytes
Cell proliferation
Biological Products
Dimers
Autoimmune Diseases
Cell Proliferation
Data storage equipment
Molecules
khellinone

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

A new class of blockers of the voltage-gated potassium channel Kv1.3 via modification of the 4- or 7-position of khellinone. / Harvey, Andrew J.; Baell, Jonathan B.; Toovey, Nathan; Homerick, Daniel; Wulff, Heike.

In: Journal of Medicinal Chemistry, Vol. 49, No. 4, 23.02.2006, p. 1433-1441.

Research output: Contribution to journalArticle

Harvey, Andrew J. ; Baell, Jonathan B. ; Toovey, Nathan ; Homerick, Daniel ; Wulff, Heike. / A new class of blockers of the voltage-gated potassium channel Kv1.3 via modification of the 4- or 7-position of khellinone. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 4. pp. 1433-1441.
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