Design, synthesis, and biological evaluation of 1,3-dioxoisoindoline-5-carboxamide derivatives as T-type calcium channel blockers

Article abstract of DOI:10.1016/j.bmcl.2006.10.042

A small molecule library of 1,3-dioxoisoindoline-5-carboxamides 4 was designed based on the pharmacophore model, synthesized and biologically evaluated as potential T-type calcium channel blockers. The most active compounds 4d and 4n show T-type calcium c

Full text of DOI:10.1016/j.bmcl.2006.10.042

Bioorganic & Medicinal Chemistry Letters 17 (2007) 476–481
Design, synthesis, and biological evaluation of 1,3-dioxoisoindoline-
5-carboxamide derivatives as T-type calcium channel blockers
Hwa Sil Kim,a,b Yoonjee Kim,a Munikumar Reddy Doddareddy,a Seon Hee Seo,a
Hyewhon Rhim,a Jinsung Tae,b Ae Nim Pae,a Hyunah Chooa,*, and Yong Seo Choa,*,
aLife Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea
bDepartment of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea
Received 27 June 2006; revised 25 September 2006; accepted 10 October 2006
Available online 21 October 2006
Abstract—A small molecule library of 1,3-dioxoisoindoline-5-carboxamides 4 was designed based on the pharmacophore model,
synthesized and biologically evaluated as potential T-type calcium channel blockers. The most active compounds 4d and 4n show
T-type calcium channel blocking activity with IC50 values of 0.93 and 0.96 lM, respectively.
Ó 2006 Elsevier Ltd. All rights reserved.
Influx of calcium ions into cells is involved in numerous
intracellular events. Calcium ions are required for con-
traction of skeletal muscle and heart, release of neuro-
transmitters and hormones, induction of cell death,
activation of various protein kinases and signaling cas-
cades, and so on.1 Precise control of calcium influx is
therefore critical. Calcium influx is regulated by various
calcium channels, mainly voltage-dependent calcium
channels and ligand-dependent calcium channels.2 Volt-
age-dependent calcium channel is a principal route
through which calcium ions enter the cytosol. Voltage-
dependent calcium channels are divided into high-volt-
age activated (N-, L-, P/Q, and R-type) and low voltage
activated (T-type) channels based on the amount of cel-
lular depolarization required for activation.2
mibefradil, was used in treatment of hypertension and
stable angina pectoris with much less side effects than
L-type calcium channel blockers (Fig. 1).5 However,
mibefradil was briefly marketed under the trade name
PosicorTM and withdrawn because of unfavorable drug–
drug interactions.6
In addition to the cardiovascular effects, T-type calcium
channels play crucial roles in the control of neuropathic
pains which are caused mainly by hyperexitable neu-
rons.7 T-Type calcium channel blockers such as ethosux-
imide and methsuximide are efficacious for treatment of
epilepsy and absence seizure derived from hyperexitable
neurons (Fig. 1).8,9 Evidences have been accumulated
that T-type calcium channel blockers are efficacious in
the treatment of neuropathic pain.8,10 T-type calcium
channels have also been reported to be involved in
various intracellular events such as neuronal differentia-
tion,11 cisplatin-induced apoptosis,12 and p21ras signal-
ing pathway.13
Agents which inhibit or activate calcium channels have
been shown to be useful as therapies for treating a wide
variety of diseases and disorders.3 Calcium channel
blockers are the most widely used class of drugs in the
treatment of cardiovascular diseases such as hyperten-
sion and angina pectoris.4 These calcium channel block-
ers mainly block L-type calcium channel and show side
effects such as bradycardia and atrioventricular block.4
On the other hand, a T-type calcium channel blocker,
Since the withdrawal of mibefradil and the increased
interest in the T-type calcium channels as a therapeutic
target, there have been significant efforts to develop
selective T-type calcium channel blockers.14 Herein we
report design, synthesis, and biological evaluation of
novel T-type calcium channel blockers.
Keywords: T-type calcium channel blockers; 1,3-Dioxoisoindoline-5-
carboxamides; Pharmacophore model.
To design novel T-type calcium channel blockers, (1) a
pharmacophore model was generated from active
compounds,15 (2) core features were defined to find a
*
Corresponding authors. Tel.: +82 2 958 5157; fax: +82 2 958 5189;
e-mail addresses: ys4049@kist.re.kr; hchoo@kist.re.kr
These co-corresponding authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.042

H. S. Kim et al. / Bioorg. Med. Chem. Lett. 17 (2007) 476–481
477
OMe
N
H
O
O
O
F
N
O
O
O
N
N
NH
Me
mibefradil
ethosuximide
methsuximide
Figure 1. T-type calcium channel blockers.
minimum scaffold, (3) building blocks were attached to
the scaffold to match other common features from the
pharmacophore model, and (4) a small molecule library
was generated. A pharmacophore model was generated
by using the in-house hits obtained from commercial li-
braries15d as well as active compounds from litera-
tures.14,15c Analysis of the pharmacophore model gave
six common features such as two hydrogen bond accep-
tors, one positively ionizable point, and three hydropho-
bic centers (Fig. 2). The two hydrogen bond acceptors
and the middle hydrophobic center were assigned as core
indoline-5-carboxylic acids 3 in 58–96% yields. The car-
boxylic acids 3 were converted to the corresponding acyl
halides by using oxalyl chloride and a catalytic amount
of DMF in anhydrous CH2Cl2. Treatment of the crude
acyl halides with N-aminoalkyl-piperidine, pyrrolidine
or morpholine (R2NH2, Scheme 2) in CH2Cl2 provided
1,3-dioxoisoindoline-5-carboxamide derivatives 1, which
were treated with 1 N HCl in ethereal solution to give
the corresponding HCl salts 4 in 17–98% overall yields
starting from the carboxylic acids 2 (Scheme 2).
features,
and
1,3-dioxoisoindoline-5-carboxamide,
Total 132 compounds of 4 were synthesized with combi-
nation of two building blocks, R1 and R2. The biological
activity of the synthesized compounds was evaluated
against HEK293 cells which stably express both T-type
calcium channel Cav3.1 with a1G subunit and potassium
channel Kir2.1.16 The % inhibition of Ca2+ current was
measured at certain molar concentration of the synthe-
sized compounds. For this purpose, two assay methods
were employed: FDSS6000 assay17 and patch–clamp as-
say using a single cell16. FDSS6000 assay is developed
for high-throughput screening and applied to the whole
small molecule library. On the other hand, patch–clamp
assay is more accurate and sensitive but measures Ca2+
current one by one. The synthesized 132 compounds
were primary-screened by FDSS6000 assay and selected
compounds with potent activity were secondary-
screened by patch–clamp assay to obtain IC50 values
(Table 1).
which could be easily constructed starting from the com-
mercially available sources, was selected as the minimum
scaffold (Scheme 1). The 1,3-dioxoisoindoline-5-carbox-
amide has two hydrogen bond acceptors properly
positioned and one hydrophobic center in the middle.
Two building blocks, R1 and R2, were attached to the
1,3-dioxoisoindoline-5-carboxamide core. One building
block R1 with substituted phenyl or benzyl groups consti-
tutes a hydrophobic center, while the other building
block R2 has saturated heterocyclic tertiary amines corre-
sponding to the positively ionizable point and hydropho-
bic center in the far right side of the pharmacophore
model (Fig. 2). By combination of various R1 and R2, a
small molecule library of T-type calcium channel
blockers was constructed (Scheme 1). One of the
designed compounds was mapped to the pharmacophore
model, which was well-positioned with satisfying the six
common features of the pharmacophore model (Fig. 3).
The preliminary calcium channel blocking activity of the
synthesized compounds was obtained by FDSS6000
assay. The FDSS6000 assay results are summarized as
follows: first, in general, 1,3-dioxoisoindoline-5-carbox-
amide derivatives 4 with benzyl group as R1 are more
potent than the corresponding phenyl-substituted ana-
logs. Compounds 4 with fluorobenzyl groups as R1
show T-type calcium channel blocking activity in 30–
86% inhibition range at 100 lM, while compounds 4
with fluorophenyl groups are active only with 15–46%
inhibition range at 100 lM (detailed data not shown).
Second, biological activity also depends on R2 groups,
in which compounds 4 with piperidine-based group are
more active than those with pyrrolidine group or rela-
tively polar morpholino group. Third, the alkyl tether
of R2, either propylenes or ethylenes within 3-(2-meth-
ylpiperidino)-propyl and 2-piperidinoethyl groups, gives
little effect on the inhibition of T-type calcium current.
The designed T-type calcium channel blockers of the
small molecule library were synthesized from commer-
cially available 1,2,4-benzenetricarboxylic acid anhy-
dride 2 (Scheme 2). 1,2,4-Benzenetricarboxylic acid
anhydride 2 was treated with various anilines and ben-
zylamines (R1NH2, Scheme 2) in acetic acid under
refluxing conditions to give 2-substituted 1,3-dioxoiso-
Figure 2. A pharmacophore model generated from hits and known
active compounds. The features are shown in green (hydrogen
acceptors), red (a positively ionizable point), and cyan (hydrophobic
centers), respectively.
Based on the preliminary information of the activities
from the FDSS assay, 20 compounds were selected
and biologically evaluated with patch–clamp assay

478
H. S. Kim et al. / Bioorg. Med. Chem. Lett. 17 (2007) 476–481
O
O
R2
N
R1
N
H
1
O
F
F
Cl
Cl
R1 =
F
Cl
a
b
c
d
e
f
g
CH3
OCH3
CH3
OCH3
CH3
OCH3
j
m
h
i
k
l
F
Cl
F
F
a'
b'
c'
d'
e'
CH3
Cl
CH3
CH3
Cl
g'
j'
f'
h'
i'
OCH3
OCH3
OCH3
CN
k'
l'
m'
n'
R2 =
3-(2-methylpiperidino)-propyl (i)
N
3-pyrrolidinopropyl (ii)
3-morpholinopropyl (iii)
N
O
N
2-piperidinoethyl (iv)
N
2-pyrrolidinoethyl(v)
2-morpholinoethyl (vi)
N
O
N
Scheme 1. Designed T-type calcium channel blockers with 1,3-dioxoisoindoline-5-carboxamide scaffold.
method to obtain IC50 values. The results are shown in
Table 1. The selected compounds have substituted ben-
zyl groups at R1 and piperidine-based groups at R2 ex-
cept the compound 4t which has
a pyrrolidine
substituent. According to the SAR study of the aromatic
substituents of R1, substituted benzyl groups show bet-
ter blocking activity of T-type calcium current than a
benzyl group without substitution (entry 8, 4h). Among
the aromatic substituents, chlorobenzyl groups (4b–d
and 4l–n) show better T-type blocking activity than
the other substituted benzyl groups such as fluoro,
methyl, and methoxy. Particularly, compounds 4d and
Figure 3. The mapping of one of designed compounds to the
phamacophore model.

H. S. Kim et al. / Bioorg. Med. Chem. Lett. 17 (2007) 476–481
479
4n18 with a p-chlorobenzyl group as R1 show the most
potent blocking activity of T-type calcium current with
an IC50 values of 0.93 and 0.96 lM, respectively, which
are comparable to that of mebefradil, the positive con-
trol. Aromatic methyl substituents (4e–g and 4o–q) also
show moderate to potent activity. However, unlike 4d
and 4n, compounds 4f and 4p with a methyl substituent
at meta position instead of para show potent activity
with an IC50 values of 1.84 and 1.93 lM, respectively.
On the other hand, compounds 4 with a fluorobenzyl
group (4i–k) or a methoxybenzyl group (4r and 4s) show
only moderate activity, except compound 4a which has
relatively potent activity with IC50 value of 2.03 lM.
For the R2 group, the 3-(2-methylpiperidino)-propyl-
substituted analogs (4a–g) are generally more potent
than the 2-piperidinoethyl-substituted ones (4h–s). Com-
pound 4t with 3-pyrrolidinopropyl group at R2 shows
O
O
O
O
R1-NH2
AcOH
OH
OH
O
R1
N
O
O
2
3
i) cat. DMF, (COCl)2
CH2Cl2
ii) R2-NH2, CH2Cl2
iii) 1N HCl in Et2O
O
O
R2
N
R1
N
H
O
HCl salt
4
Scheme 2. Synthesis of the small molecule library.
Table 1. T-type calcium channel blocking activity of selected 1,3-dioxoisoindoline-5-carboxamide derivatives 4 by patch–clamp assay
O
O
R2
N
R1
N
H
O
HCl salt
4
R1
R2
IC50 (lM)
a
Entry
1
Compound
4a
p-F-benzyl
o-Cl-benzyl
m-Cl-benzyl
p-Cl-benzyl
o-Me-benzyl
m-Me-benzyl
p-Me-benzyl
Benzyl
2.03 0.12
1.52 0.19
N
N
N
N
N
N
N
2
4b
4c
4d
4e
4f
3
1.81 0.46
4
0.93 0.06
5
2.07 0.45
6
1.84 0.21
7
4g
4h
4i
3.53 0.43
8
22.78 9.23
N
N
N
N
9
o-F-benzyl
m-F-benzyl
p-F-benzyl
14.86 1.12
10
11
4j
8.52 0.75
4k
8.88 1.89
(continued on next page)

480
H. S. Kim et al. / Bioorg. Med. Chem. Lett. 17 (2007) 476–481
Table 1 (continued)
a
Entry
Compounds
R1
R2
IC50 (lM)
12
13
14
15
16
17
18
19
20
21
4l
o-Cl-benzyl
5.82 0.82
4.09 1.55
0.96 0.07
8.28 2.95
1.93 0.23
5.82 0.35
14.12 2.06
5.25 0.80
1.62 0.16
1.34 0.49
N
N
N
N
N
N
N
N
4m
4n
4o
4p
4q
4r
m-Cl-benzyl
p-Cl-benzyl
o-Me-benzyl
m-Me-benzyl
p-Me-benzyl
m-OMe-benzyl
p-OMe-benzyl
p-Cl-benzyl
Mibefradil
4s
4t
N
a IC50 value ( SD) was obtained from a dose–response curve.
Table 2. Selectivity of compounds 4d and 4n against N-type calcium channel
SIb
Cytotoxicity CC50 (lM)
a
a
c
Entry
Compound
T-type IC50 (lM)
N-type IC50 (lM)
1
2
4d
4n
0.93 0.06
0.96 0.07
54.72 6.81
33.40 4.16
59
35
>100
>100
a IC50 value ( SD) was obtained from a dose–response curve.
b SI (selectivity index) = N-type IC50 value/T-type IC50 value.
c MTT assay with 0.1% DMSO as negative control and H2O2 as positive control.
potent T-type blocking activity with IC50 value of
1.62 lM, but it is less active than compounds 4d and
4n, which have piperidine-based R2 group and the same
R1 group.
alkyl tethers in R2 groups and the position of substitu-
ents in benzyl groups. For the R2 groups, piperidine-
based groups show better activity than pyrrolidine-
based groups and morpholine-based groups. The alkyl
tethers of the R2 groups prefer propylenes to ethylenes,
based on the IC50 values by patch–clamp assay.
In our efforts to identify novel T-type calcium channel
blockers, a small molecule library of 1,3-dioxoisoindo-
line-5-carboxamide derivatives 4 were designed, synthe-
sized, and biologically evaluated by FDSS6000 assay
and patch–clamp assay. Several structure–activity rela-
tionships were identified from this study. The R1 group
prefers benzyl groups to phenyl groups. Among the para
substituents in benzyl groups, the T-type blocking activ-
ity order is Cl > OMe ꢀ Me > F > H within 2-piperidi-
noethyl groups as R2, and the activity order is
Cl > F > Me > H within 3-(2-methylpiperidino)-propyl
groups as R2. Among the meta substituents, the activity
order is Me > Cl > F > OMe > H within a 2-piperidino-
ethyl group as R2. There exists a little bit difference in
the T-type blocking activity according to the length of
N-type calcium channel is one of high-voltage activated
channels, while T-type calcium channel is a low-voltage
activated channel. To determine the selectivity of the
most active compounds 4d and 4n for calcium channels,
the two compounds were further biologically evaluated
against N-type calcium channel along with cytotoxicity
(Table 2). The compounds 4d and 4n show much less
N-type calcium channel blocking activity with IC50 val-
ues of 54.72 and 33.40 lM, respectively, than T-type cal-
cium channel blocking activity. The compounds 4d and
4n are selective to T-type calcium channel without cyto-
toxicity up to 100 lM. N-type calcium channel blockers
are being developed for the treatment of severe chronic

H. S. Kim et al. / Bioorg. Med. Chem. Lett. 17 (2007) 476–481
481
pain for cancer or AIDS patients.19 On the other hand,
T-type calcium channel blockers are usually for the
treatment of migraine.19 Therefore, the selectivity be-
tween two calcium channels may be very important.
2006, 14, 3502; (b) Furukawa, T.; Yamada, O.; Matsum-
oto, H.; Yamashita, T. WO2005051402, 2005; (c) Rhim,
H.; Lee, Y. S.; Park, S. J.; Chung, B. Y.; Lee, J. Y. Bioorg.
Med. Chem. Lett. 2005, 13, 283; (d) McCalmont, W. F.;
Heady, T. N.; Patterson, J. R.; Lindenmuth, M. A.;
Haverstick, D. M.; Gray, L. S.; MacDonald, T. L. Bioorg.
Med. Chem. Lett. 2004, 14, 3691; (e) Jung, H. K.;
Doddareddy, M. R.; Cha, J. H.; Rhim, H.; Cho, Y. S.;
Koh, H. Y.; Jung, B. Y.; Pae, A. N. Bioorg. Med. Chem.
2004, 12, 3965; (f) Kumar, P. P.; Stotz, S. C.; Parama-
shivappa, R.; Beedle, A. M.; Zamponi, G. W.; Rao, A. S.
Mol. Pharmacol. 2002, 61, 649.
In summary, a new series of 1,3-dioxoisoindoline-5-car-
boxamide derivatives 4 were designed, synthesized, and
biologically evaluated to develop novel effective T-type
calcium channel blockers. Among total 132 compounds,
4d and 4n show the most potent T-type calcium channel
blocking activity. Further evaluations of compounds 4d
and 4n such as pharmacokinetics and neuronal analgesic
effect are in progress.
15. (a) Doddareddy, M. R.; Jung, H. K.; Cha, J. H.; Cho, Y.
S.; Koh, H. Y.; Chang, M. H.; Pae, A. N. Bioorg. Med.
Chem. 2004, 12, 1613; (b) Doddareddy, M. R.; Jung, H.
K.; Lee, J. Y.; Lee, Y. S.; Cho, Y. S.; Koh, H. Y.; Pae, A.
N. Bioorg. Med. Chem. 2004, 12, 1605; (c) Doddareddy,
M. R.; Choo, H.; Cho, Y. S.; Rhim, H. Y.; Koh, H. Y.;
Lee, J. -H.; Jeong, S. W.; Pae, A. N. Bioorg. Med. Chem.,
2006, in press.; (d) In-house hit generation method: the in-
house libraries of compounds were biologically tested
against T-type calcium channel. Among those compounds,
most active compounds were selected and a pharmaco-
phore model was generated by using common feature
hypothesis generation approach (HipHop) implemented in
CATALYST 4.11 software package (Accelrys Software
Inc., San Diego, CA).15b Using this pharmacophore, we
virtually screened commercially available Ion channel
(ChemDiv Inc.) and Maybridge2001 (maybridge.com)
databases, selected virtual hits which were tested for
blocking effect on T-type calcium channel. The best
compound was selected for the new pharmacophore
generation along with other in-house hit compounds with
IC50 values of about 0.1 lM. With those compounds, a
new pharmacophore was generated by using HipHop
(Fig. 2).
Acknowledgment
This work was supported by Korea Institute of Science
and Technology (2E18970).
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DMSO-d6) d 10.36 (br s, 1H), 9.15–9.02 (m, 1H), 8.39–8.22
(m, 2H), 7.99 (d, 1H, J = 7.8 Hz), 7.43–7.22 (m, 4H), 4.77
(s, 2H), 3.63–3.50 (m, 0.3H), 3.49–3.30 (m, 2H), 3.30–2.96
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(m, 5H), 1.55–1.38 (m, 1H), 1.28 (d, 2.1H, J = 6.0 Hz),
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58.68, 51.44, 50.19, 47.41, 37.39, 31.37, 22.98, 22.21, 17.64;
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1
Found 454.1887: for compound 4n (HCl salt), H NMR
(400 MHz, DMSO-d6) d 10.26 (br s, 1H), 9.29 (t, 1H,
J = 5.0 Hz), 8.39–8.28 (m, 2H), 7.99 (d, 1H, J = 8.1 Hz),
7.42–7.26 (m, 4H), 4.77 (s, 2H), 3.78–3.64 (m, 2H), 3.58–
3.41 (m, 2H), 3.29–3.13 (m, 2H), 2.98–2.82 (m, 2H), 1.89–
1.61 (m, 5H), 1.43–1.29 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) d 167.61, 167.55, 165.27, 139.74, 135.96,
134.33, 134.25, 132.56, 132.31, 129.87, 129.01, 123.88,
122.28, 55.49, 52.62, 34.72, 22.75, 21.75; HRMS (FAB,
M+1) Calcd for C23H25ClO3N3: 426.1576. Found
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