Biomedical Engineering Reference
In-Depth Information
N
CH
3
O
O
CH
3
O
H
29
N
CH
3
O
O
S
O
CH
3
H
30
Among these series
K
v
1.5
blockers, AVE0118 (24) was able to decrease
the steady-state
hK
v
1.5
current and prolong APD to enhance atrial contractility
[
72
,
73
]. Besides it can also prolong the atrial effective refractory period (AERP) in
anesthetized pigs and conscious goats without any change on the QT interval of the
ECG and any possibility of inducing TdP [
74
-
76
]. Recently, the micropuncture
studies of atrial human tissues in chronic AF patients exhibited that AVE0118 could
increase the plateau potential and prolong the APD by 20 ms at a concentration of
6
M[
77
].
Another interesting compound, S9947 (25), could block the cloned human
K
v
1.5
channel current expressed in
Xenopus oocytes
and CHO cells with IC
50
values of 0.6
m
Mand0.4
M, respectively [
78
]. Moreover, at a concentration
m
m
of 3
M, S9947 is served as sodium channel inhibitor since no influence on the
upstroke of the action potential was observed [
79
]. S9947 could also prolonged
rat ventricular action potential at both slow- and fast-pacing rates without any
influence on
h
ERG channels. Being considered as multiple ion channel blockers,
S9947 and S20951 (26) are thought to be prior to current available class III anti-
arrhythmic agents as their maximal APD prolongation at slow rates and minimal
effects during tachycardia. Therefore, this series of blockers might have a supe-
rior antiarrhythmic profile in human atrial cells and could bear a promising
strategy against AF [
80
].
m
3.3.6 Anthranilic Amide Derivatives
Researchers in Aventis established a three-hydrophobic-point pharmacophore
model (Fig.
3
) based on the biphenyl compounds 31 (IC
50
¼
0.2
M) and 32
m
(IC
50
¼
M). After 3D similarity search on Aventis in-house compound col-
lection, Peukert et al. reported a new series of anthranilic amides as
K
v
1.5
blockers
(33)[
81
]. The discovery of compound 33 (IC
50
¼
2.8
m
M) was recognized as
the application of an innovative scaffold hopping strategy [
82
] based on the
5.6
m
