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 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 language | English (US) |
|---|---|
| Pages (from-to) | 2326-2336 |
| Number of pages | 11 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 47 |
| Issue number | 9 |
| DOIs | |
| State | Published - Apr 22 2004 |
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ASJC Scopus subject areas
- Organic Chemistry
Cite this
Khellinone Derivatives as Blockers of the Voltage-Gated Potassium Channel Kv1.3 : Synthesis and Immunosuppressive Activity. / Baell, Jonathan B.; Gable, Robert W.; Harvey, Andrew J.; Toovey, Nathan; Herzog, Tanja; Hänsel, Wolfram; Wulff, Heike.
In: Journal of Medicinal Chemistry, Vol. 47, No. 9, 22.04.2004, p. 2326-2336.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Khellinone Derivatives as Blockers of the Voltage-Gated Potassium Channel Kv1.3
T2 - Synthesis and Immunosuppressive Activity
AU - Baell, Jonathan B.
AU - Gable, Robert W.
AU - Harvey, Andrew J.
AU - Toovey, Nathan
AU - Herzog, Tanja
AU - Hänsel, Wolfram
AU - Wulff, Heike
PY - 2004/4/22
Y1 - 2004/4/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=1842729411&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1842729411&partnerID=8YFLogxK
U2 - 10.1021/jm030523s
DO - 10.1021/jm030523s
M3 - Article
C2 - 15084131
AN - SCOPUS:1842729411
VL - 47
SP - 2326
EP - 2336
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 9
ER -