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

Harvey, AJ; Baell, JB; Toovey, N; Homerick, D; Wulff, H

Author(s): Harvey, AJ; Baell, JB; Toovey, N; Homerick, D; Wulff, H;
Details: Publication Year 2006-02-23,Volume 49,Issue #4,Page 1433-1441
Journal Title: JOURNAL OF MEDICINAL CHEMISTRY
Publication Type: Journal Article
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, la, 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.
Publisher: AMER CHEMICAL SOC
Keywords: EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; C-TYPE INACTIVATION; T-CELL ACTIVATION; K+ CHANNEL; MULTIPLE-SCLEROSIS; SHK TOXIN; INHIBITOR; LYMPHOCYTES; MECHANISM; IMMUNOMODULATION
Publisher's Version: https://doi.org/10.1021/jm050839v
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2006-02-23 12:00:00