P. Hewawasam et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1615–1618
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Table 1. Structure of 3-amino-4-benzylquinolin-2-one derivatives and effect on KCNQ2-mediated outward current in Xenopus laevis oocytes
expressing the cloned mKCNQ2
Compda
R1
R2
R3
R4
R5
R6
R
% Increase in mKCNQ2 current
@ 20 mM (@À40 mV)b
11a
12a
12b
H
H
H
H
H
CF3
H
CF3
H
H
H
H
H
OH
OH
H
Cl
Cl
H
H
H
103Æ4 (n=3)
122Æ11 (n=5)
89Æ1 @ 1 mM (n=5)
Insol. @ 5 or 20 mM
131Æ3 (n=5)
13a
13b
13c
13d
13e
14a
14b
H
H
H
H
H
H
H
H
H
H
H
CF3
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
H
H
H
H
Cl
Cl
H
SO2CF3
SO2CF3
SO2CF3
SO2CF3
SO2CF3
SO2CF3
SO2CF3
CF3
CF3
H
CF3
CF3
CF3
223Æ12 (n=5)
254Æ17 (n=5)
231Æ24 (n=7)
220Æ22 (n=6)
OH
OH
277Æ15 (n=5)
H
Cl
271Æ21 (n=6)
190Æ10 @ 1 mM (n=5)
284Æ14 (n=7)
14c
H
H
CF3
H
OH
Cl
SO2CF3
217Æ6 @ 1 mM (n=5)
143Æ6 @ 100 nM (n=5)
269Æ10 (n=3)
1 (Retigabine)
1
a All new compounds were characterized by H NMR, LRMS, and elemental analysis.
b All recordings were measured at À40 mV.
The structure–activity relationship data presented in
Table 1 provide a rudimentary understanding of the
KCNQ2 channel opening pharmacophore of 3-amino-
4-benzylquinolin-2-ones. In this preliminary study, the
optimal substitution pattern required for KCNQ2
channel opening activity was probed. Unsubstituted
3-amino-4-benzylquinolin-2-one (11a) was inactive.
Incorporation of CF3 group and 5-chloro-2-hydroxy-
benzyl moiety (12a) resulted in a slight increase in
channel opening activity. Similarly, derivatization of the
3-amino group as (trifluoromethyl)sulfonamide (13a)
also had modest enhancement of channel opening
activity. However, the most dramatic improvement in
KCNQ2 channel opening activity was observed upon
incorporation of these three elements together onto the
3-amino-4-benzylquinolin-2-one pharmacophore. It is
also apparent that (trifluoromethyl)sulfonamido group
and CF3 moiety work in tandem to exert the biggest
enhancement in channel opening activity. This observa-
tion indicates an important relationship between
increasing acidity of the 3-amino moiety and enhanced
channel opening activity. Additionally, both methoxy
and hydroxy moieties also enhance the channel opening
activity. Removal of the chlorine atom as shown in 14a
did not affect the opening activity. A majority of the
sulfonamide derivatives (13b–e, 14a–c) were shown to
be efficacious KCNQ2 channels openers with greater
than 200% increase in outward currents at 20 mM. In
comparison, these novel KCNQ2 openers are approach-
ing or, in some cases, equaling the efficacy of Retigabine
(1). The most potent KCNQ2 opener (14c) identified
from this series showed robust opening of the channel
even at 100 nM. The EC50 value of 14c was determined
to be 663 nM.
both an electron-withdrawing substituent on the quino-
lone nucleus and the presence of a phenolic hydroxyl for
effective activation of KCNQ2 channels.
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In summary, we have identified a novel class of KCNQ2
channel openers and demonstrated that channel opening
activity is enhanced by the presence of a (trifluoro-
methyl)sulfonamido group. The preliminary structure–
activity data for this series suggests the importance of