Biomedical Engineering Reference
In-Depth Information
postulated homology model for
K
v
1.5
potassium channel, will be used to guide
designing new blockers with pre-determined blocking activity and selectivity [
93
].
3.4 Other K
v
1.5 Blockers in Clinical Trials
3.4.1 Vernakalant (RSD-1235)
Vernakalant, a mixed sodium and potassium channel blockers [
94
,
95
], is an atrial-
selective antiarrhythmic drug developed by Cardiome Pharma and Astellas Pharma
[
96
-
98
]. As simple three-hydrophobic-point
K
v
1.5
blockers, Vernakalant also
shared similar framework with ICA-32 (1) but with better pharmacokinetic profiles.
In this case, its stronger alkalinity triggers more interests for medicinal chemists.
The phase I trial for controlled-release oral formulation of Vernakalant has been
successfully completed in 2005. An oral formulation was then developed in phase II
clinical phase as a chronic-use product for the maintenance of normal heart rhythm
following the termination of AF symptom. This oral controlled-release formulation
of Vernakalant was expected to help prevent or slow down the recurrence of Atrial
Fibrillation (AF), and would be used as a follow-on therapy to intravenous
Vernakalant. The safety and efficacy of intravenous Vernakalant in phase III
study in approximately 120 AF patients from 30 centers in the USA, Canada and
Europe [
99
] was carried out since 2005 and now Vernakalant is in pre-registration
phase in American Food and Drug Administration (FDA).
O
O
CH
3
CH
3
O
N
HCl
OH
Vernakalant
3.4.2 AZD7009
AZD7009, developed by AstraZeneca, was highly potent in terminating atrial fibril-
lation and flutter in anesthetized dog model [
100
]. AZD7009 blocked both
h
ERG
channel current (IC
50
¼
M).
Persson et al
.
proposed that the combined current blockade underlies the pro-
longation of the refractoriness and the low proarrhythmic activity in vivo [
101
].
In the dilated rabbit atria, AZD7009 could increase AERP in a concentration
dependent manner associated with effectively prevent AF induction and rapidly
restore sinus rhythm [
102
]. In all, AZD7009 exhibited dose-dependent effects
0.6
M) and
hNa
v
1.5
channel current (IC
50
¼
4.3
m
m
