Biomedical Engineering Reference
In-Depth Information
A comparative molecular field analysis (CoMFA) [
90
] made for a series of
Diltiazem-like channel blockers suggested that they can interact with the receptor
as its negative charge site, two hydrogen-bonding sites and three hydrophobic
regions. Campiani and co-researchers [
91
] also suggested that substitution on the
fused phenyl ring (R
4
) and the double substitution at C4 were beneficial to the
activity as well as the substitution of the electron withdrawing group in the fused
phenyl ring. In addition, the substituted phenyl ring at C4 and the basic side chain at
C1 on the pyrrole ring were found to constitute two important pharmacophores [
91
]
(Fig.
12
).
Two more pharmacophores were also identified by Kimball [
92
]: the basic
nitrogen and the phenyl methyl ethers. In particular, the selective chronotropic
and inotropic activity of new compounds might open new perspectives in the search
for more effective drugs for the control of cardiac arrhythmias and led attention to
the synthesis of novel Diltiazem-like calcium channels blockers [
72
,
93
-
95
].
2.2.3 Nonselective Calcium Ions Channel Blockers: T-Type Calcium
Channel Blockers-Structure-Activity Relationships - Molecular
Features
Mibefradil
), bepridil, fluspirilene, and
fendiline are considered as
nonselective
calcium blockers (Fig.
13
).
Furthermore,
Mibefradil
is an important example of the selective T-type calcium
channel blockers and it has been used as the first selective T-type calcium channel
blocker in treatment of hypertension and stable angina [
4
,
19
,
96
,
97
]. Depending
on the cell type, mibefradil blocks T-type calcium channels 10-30 times more
potently than
L
-type calcium channels [
98
]. In addition, mibefradil is highly tissue
selective, relaxing smooth muscle without inducing reflex tachycardia, or having
much effect on cardiac chronotropy or inotropy [
99
,
100
].
Mibefradil
because of
potential harmful interactions with other drugs [
101
] has been withdrawn from the
US market (May 1998) very shortly. Continuous structure-activity relationship
studies on 3, 4-dihydroquinazoline series led to the synthesis of KYS05090 [
102
]
(Fig.
14
), which is a very potent blocker (IC
50
¼
(IC
50
¼
1.34
0.49
M; Posicor
m
™
1 nM) against T-type
calcium channel and also is as potent as doxorubicin against some human cancer
cells without acute toxicity [
103
,
104
].
41
O
OCH
3
O
H
N
N
F
N
Fig. 13 Mibefradil
