Biomedical Engineering Reference
In-Depth Information
The succeeding sections of this review summarize QSAR studies carried out on
different chemical scaffolds in modulating the activity of various potassium ion
channels. Each section is identified with the leading chemical scaffold. Most of the
articles reviewed belong to preceding 5-7 years. They provide critical inputs for
modulating the biological endpoints of chemical entities in terms of the potential
structural modifications.
2.1 Benzodiazepine Derivatives
Late 1990s has seen considerable research activity in the discovery of chemical
prototypes, which can activate or block the potassium channels [
12
]. In antiarrhyth-
mic agents, Class I agents interfere with sodium channels, Class II agents (
b
blockers) are anti-sympathetic nervous system agents and Class III agents interfere
with potassium (K
+
) efflux [
28
]. The cardiac arrhythmia suppression trial has
shown that treatment of arrhythmias with Class I agents lead to higher deaths
than with placebo [
29
]. This has prompted a search for compounds, which exert
antiarrhythmic effects through other pathways. The Class III antiarrhythmic agents
work through delaying repolarization of cardiac myocytes. The cardiac rectifier
potassium ion current,
I
K
, contributes to repolarization in two kinetically distinct
ways namely, a rapidly activating ion current
I
Kr
and a slowly activating ion current
component
I
Ks
. Selective blockade of either
I
Kr
or
I
Ks
would lead to a prolongation
of the refractory period. A selective blocking of
I
Ks
is more safer than blocking
I
Kr
channel [
30
,
31
]. While benzodiazepines were probed as cholecystokinin-B recep-
tor antagonists, some analogues markedly increased the electrocardiographic QT
interval in dogs. Thus, benzodiazepines were further explored as potential blocker
of
I
Ks
. This has led to (R)-2-(2,4-trifluoromethyl)-N-[2-oxo-5-phenyl-1-(2,2,
2-trifluoroethyl)-2,3-dihydro- 1H-benzo[e][1,4]diazepin-3-yl]acetamide (L-768,673)
(1;X
CH
2
-2,4-diCF
3
-Ph), an orally active, potent and selec-
tive
I
Ks
blocking agent [
32
].
¼
F
3
CCH
2
and Y
¼
X
O
N
NH
N
Y
O
1
In view of its importance, Gupta and coworkers [
33
] have investigated the
rationale behind the
I
Ks
blocking activity of these benzodiazepine derivatives (1)
with simple molecular connectivity indices (1). In these compounds, X is either
alkyl, fluoroalkyl, alkylamine or hydrogen, and Y is substituted aryls and cyclo-
hexyls linked through methylene/ethylene spacers.
