3,4-Dihydroquinazoline derivatives as novel selective T-type Ca 2+ channel blockers

Article abstract of DOI:10.1016/j.bmcl.2004.04.090

For LVA T-type Ca²⁺ channel blockers, 3,4-dihydroquinazoline derivatives as new scaffolds were prepared and evaluated for the inhibitory activity against two members of the recombinant T-type Ca²⁺ channel family. Among them, 8a (KYS0

Full text of DOI:10.1016/j.bmcl.2004.04.090

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3379–3384
3,4-Dihydroquinazoline derivatives as novel selective T-type Ca2þ
channel blockers
Yong Sup Lee,a Bum Hoon Lee,a,b Seong Jun Park,a,b Soon Bang Kang,a Hyewhon Rhim,a
Jin-Yong Park,c Jung-Ha Lee,c Seong-Woo Jeongd and Jae Yeol Leee,*
aLife Sciences Division, Korea Institute of Science & Technology, PO Box 131, Cheongryang, Seoul 130-650, South Korea
bDepartment of Chemistry, Korea University, 1-Anamdong, Seoul 136-701, South Korea
cDepartment of Life Science, Sogang University, Shinsu-1-Dong, Seoul 121-742, South Korea
dDepartment of Physiology and Institute of Basic Medical Science, Yonsei University, Wonju College of Medicine,
Ilsan-Dong 162, Wonju, Kangwon-Do 220-701, South Korea
eResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University,
1 Hoegi- Dong, Seoul 130-701, South Korea
Received 9 April 2004; revised 27 April 2004; accepted 28 April 2004
Available online
Abstract—For LVA T-type Ca2þ channel blockers, 3,4-dihydroquinazoline derivatives as new scaffolds were prepared and evaluated
for the inhibitory activity against two members of the recombinant T-type Ca2þ channel family. Among them, 8a (KYS05001,
IC50 ¼ 0.9 lM) was nearly equipotent with mibefradil (IC50 ¼ 0.84 lM) and inhibited LVA T-type Ca2þ channel with greater efficacy
than HVA Ca2þ channel.
Ó 2004 Elsevier Ltd. All rights reserved.
Low voltage-activated (LVA) Ca2þ channels are
strongly associated with the generation of rhythmical
firing patterns in the mammalian CNS.1–3 Furthermore,
many reports have suggested that T-type channels are
implicated in pathogenesis of epilepsy and neuropathic
pain.4–7 This view is supported by an antiepiletic drug
that is known to alleviate the generation of neuronal
hyperexcitability in the brain: Ethosuximide (Zaron-
tinâ), a succinimide derivative, is an anticonvulsant
effective in the treatment of absence epilepsy (Fig. 1).8;9
Until recently, three genes encoding T-type Ca2þ chan-
nel pore-forming subunits were identified and desig-
nated Cav3.1 (a1G), Cav3.2 (a1H), and Cav3.1 (a1I).10–13
However, only limited progress has been made to date in
the quest to identify both potent and selective com-
pounds for T-type channel blockade. Only Kurtoxin
(IC50 ¼ 15 nM) isolated from the scorpion and mibefra-
dil (IC50 ¼ 1 lM) developed by Roche have been known
as most potent T-type channel antagonists (Fig. 1).14–16
However, Kurtoxin also inhibits the HVA Ca2þ
O
OCH3
H3C
CH3
O
H
N
O
O
CH3
N
H
H
N
O
N
N
N
CH3
F
N
N
CH3
ethosuximide
Figure 1. Structures of T-type Ca2þ channel blockers.
mibefradil
8a (KYS05001)
Keywords: 3,4-Dihydroquinazolines; T-type calcium channel; Blockers; Mibefradil.
* Corresponding author. Tel.: +82-2-9610726; fax: +82-2-9663701; e-mail: ljy@khu.ac.kr
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.090

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Y. S. Lee et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3379–3384
channels and its peptide nature (63 amino acids) has a
problem for the therapeutic agent.17 In the meanwhile,
mibefradil is nonselective as well and regarded as a
broad spectrum ion channel blocker with activities on
HVA Ca2þ channels, Naþ channels, Kþ channels, and
ClÀ channels.18–21 As a result, mibefradil was withdrawn
from U.S. market in May 1988 due to the toxicity from
drug–drug interaction. Therefore, new T-type Ca2þ
channel blockers having new scaffolds are needed in
understanding the exact role of T-type Ca2þ channel in
cellular functions. Herein we describe the synthesis and
in vitro T-type Ca2þ channel blocking effects of 3,4-di-
hydroquinazoline derivatives for the development of
both potent and selective T-type Ca2þ channel blockers
(Fig. 1).
The in vitro calcium channel blocking activities of 3,4-
dihydroquinazoline derivatives (6a–j, 7a–d, and 8a–i)
were determined in T-type channels expressed Xenopus
oocytes (a1H) or HEK293 cells (a1G). As preliminary
assays, all synthetic compounds (100 lM) were evalu-
ated for their inhibitory effects on a1H T-type Ca2þ
channels expressed in Xenopus oocytes by a two-elec-
trode voltage clamp method.26 The compounds shown
more than 50% inhibition were re-evaluated for the
blocking effects on a1G T-type Ca2þ channels expressed
in HEK293 cells at 10 lM concentration by whole-cells
patch clamp methods.27 The molar concentrations (IC50)
of test compounds required to produce 50% inhibition
of a1G T-type currents were determined from fitting raw
data into dose–response curves. In vitro blocking effects
of all 3,4-dihydroquinazoline derivatives were summa-
rized in Table 1.
The 3,4-dihydroquinazoline derivatives (6) were pre-
pared by using a known method, as illustrated in
Scheme 1.22 Thus, carbodiimide (4), an intermediate of
this reaction, was prepared by the reaction of urea (3)
with Ph3PÁBr2 and Et3N.23 The urea (3) was prepared in
two steps starting from methyl 2-nitrocinnamate (1)
according to a published procedure.24 The regioselective
addition of secondary amine into the carbodiimide (4)
followed by intramolecular conjugate addition of the
resulting amine species (5) to an a,b-unsaturated ester
finally afforded the 3,4-dihydroquinazoline derivative
(6). The methyl ester group of compound 6 was
hydrolyzed with LiOH to provide the free carboxylic
compound 7 in quantitative yield. The acid compound 7
was coupled with alcohol or amine by using EDC and
HOBT to give the respective ester or amide as illustrated
in Scheme 1.25 The structure and yield of each step for
all compounds were summarized in Table 1.
Irrespective of the kinds of substituents at R1 and R2
position, as a glance, compounds (6a–j, 7a–d, and 8f–i)
possessing methyl or benzyl ester and free carboxylic
group at 4-position of quinazoline ring showed poor
inhibitory activities (0.0–32.7% inhibition range) against
the a1H T-type Ca2þ channel with exception of com-
pound 6d (51.5% inhibition), which has the phenyl rings
at R1 and R2 position.28 On the other hand, compounds
(8a–d) having a benzyl amide substituent always showed
good efficacies (63.8–91.9% inhibition range) except for
8e (14.8%), which was obtained from compound 6d.
Among them, the compound 8d (91.9%) bearing a
piperidine ring at R2 position and a 4-nitrobenzylamide
functional group at 4-position of quinazoline ring was
particularly more potent than the reference drug mibe-
fradil (86%). This result implies that both N-heterocycles
O
O
O
a
b
c
OCH3
OCH3
OCH3
NO2
NH2
NH
NH
O
1
2 (93%)
3a, R1 = Ph
(96%)
3b, R1 = c-Hex (90%)
3c, R1 = i-Pr (92%)
R1
O
O
OCH3
HN R1
R2
CH3O
O
R1
d
e
N
OCH3
N C N R1
N
N
R2
4a, R1 = Ph
(75%)
5
6a-j
4b, R1 = c-Hex (80%)
4c, R1 = i-Pr (90%)
O
O
R3
HO
X
R1
N
R1
R2
N
f
N
R2
N
7a-d
8a-i, X = O or NH
Scheme 1. Reagents and conditions: (a) SnCl2Á2H2O, EtOAc, 70 °C, 1 h; (b) R1NCO, benzene, rt, 12 h; (c) Ph3PÁBr2, Et3N, CH2Cl2, 0 °C, 1 h;
(d) R2H or R2MgBr, THF, rt or reflux; (e) LiOHÁH2O, THF–H2O (1:1), 60 °C, 2 h; (f) R3OH or R3NH2, HOBT, EDC, rt, 5 h.

Y. S. Lee et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3379–3384
Table 1. In vitro calcium channel blocking effects of 3,4-dihydroquinazolines derivatives
3381
O
O
O
R3
CH3O
HO
X
R1
R2
R1
R2
R1
R2
N
N
N
N
N
N
6
7
8
Compounda
Yieldb (%)
R1
R2
R3
X
Xenopus
HEK293 cells (a1G)
oocyte (a1H
)
% Inhibition
(100 lM)c
% Inhibition
(10 lM)c
IC50 (lM)d
6a
80
11.5
18.3 6.4
27.70
N
6b
6c
70
75
14.0
15.0
O
N
H3C
N
N
6de
6e
6f
51.5
27.0
12.2
3.0
50.0 3.1
10.70
50
75
50
N
O
N
6g
H3C
N
N
N
H3C
H3C
6h
6i
40
70
8.0
H3C
H3C
ꢀ0
O
N
H3C
H3C
6j
50
ꢀ0
H3C
N
N
N
8.0
7a
7b
ꢀ99
ꢀ99
9.0
O
N
15.0
H3C
N
N
N
7c
7d
ꢀ99
ꢀ99
7.2
8a
(KYS05001)
NH
NH
NH
NH
NH
77.0
90.1 2.3
40.5 5.5
29.0 0.8
92.3 1.3
0.90
21.60
35.80
2.50
60
78
8b
8c
63.8
70.3
91.9
14.8
O
N
50
60
89
H3C
N
N
N
8d
(KYS05034)
O2N
8e
(continued on next page)

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Y. S. Lee et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3379–3384
Table 1 (continued)
Compounda
Yieldb (%)
R1
R2
R3
X
Xenopus
HEK293 cells (a1G)
oocyte (a1H
)
% Inhibition
(100 lM)c
% Inhibition
(10 lM)c
IC50 (lM)d
8f
74
86
88
70
O
O
O
O
14.2
15.6
20.9
8g
8h
N
O
N
8i
32.7
86.0
H3C
N
N
Mibefradil
95.9 1.7
0.84
a All compounds were obtained as racemates.
b Isolated yield.
c % Inhibition value ( SEM) was obtained by repeated procedures ðn P 3Þ.
d IC50 value was determined from the dose–response curve.
e Compound obtained from our previous work.28
at R2 position and benzylamide group at 4-position of
quinazoline ring would be the essential pharmacophores
for calcium entry blocking activity.
(KYS05001) and 8d (KYS05034) were nearly equipotent
(90.1 2.3, 92.3 1.3% inhibition) comparable with
mibefradil (95.9 1.7% inhibition). With respect to the
IC50 values, however, the compound 8a (KYS05001,
IC50 ¼ 0.9 lM) was shown to be 2.8-fold more potent
than 8d (KYS05034, IC50 ¼ 2.5 lM) and nearly equipo-
tent with mibefradil (IC50 ¼ 0.84 lM).
Next, the effective compounds (6a, 6d, and 8a–d) were
further evaluated in HEK293 cells (a1G) at lower con-
centration (10 lM). Our experimental results are sum-
marized as follows. First, the inhibitory effects of
compounds were quite similar in HEK293 cells (a1G) as
Xenopus oocyte (a1H) except for the compound 8c, which
displayed surprisingly the decreased magnitude of inhi-
bition (29.0 0.80%) compared with the inhibitory
activity on the a1H expressed in Xenopus oocytes
(70.3%). Secondly, the structure–activity relationships
showed that the relative potency order was piperidine
(8a, 8d) > morpholine (8b) > 4-methylpiperazine (8c)
with respect to R2 substituent and the compound 8a
Based on the SAR data, we embarked on the synthesis of
8d (KYS05034) analogs in order to increase the potency
and the pharmacological profile, as illustrated in Scheme
2. Hydrogenation of the nitro group of compound 8d
using 10% Pd(C) in MeOH afforded N-(4-aminobenzyl-
amido)-3,4-dihydroquinazoline (9, KYS05040) in 97%
yield, which was coupled with the respective phen-
ylsulfonyl chloride in the presence of pyridine to provide
the sulfonamido-3,4-dihydroquinazoline derivative 10a
O
N
O
N
H
H
a
b
O2N
N
H2N
N
N
N
N
N
8d (KYS05034)
9 (KYS05040): (97%)
O
N
H
O
O
S
N
N
H
R4
N
N
10a (KYS05041), R4 = CH3 (94%)
10b (KYS05042), R4 = F (73%)
Scheme 2. Reagents and conditions: (a) 10% Pd(C), MeOH, rt, 2 h; (b) p-CH3–PhSO2Cl (for 10a), or p-F–PhSO2Cl (for 10b), pyridine, 0 °C to rt,
24 h.

Y. S. Lee et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3379–3384
3383
(KYS05041) and 10b (KYS05042), respectively, in 94%
and 73% yields. Calcium blocking effects of these analogs
(9, 10a, and 10b) were determined using two calcium
channel isoforms (a1H and a1G) and also their IC50 values
for inhibition of HEK293 cells (a1G) were determined
from the dose–response curve. In addition, these com-
pounds were screened against Naþ channels and high
voltage-activated (HVA) Ca2þ channels of major pelvic
ganglion (MPG) neurons for the evaluation of ion
channel selectivity including compounds 8a and 8d.29 All
inhibitory activity data of these compounds were sum-
marized in Table 2.30
As shown in Table 2, all compounds generally showed
less inhibitory potencies in major pelvic ganglion (MPG)
neurons than Xenopus oocytes and HEK293 cells and
these results would be caused by the dilution effect
connected with their nonspecific binding affinities for the
present background of MPG neurons. With respect to
calcium channel selectivity, all compounds except 8a
showed similar blocking effects against both LVA T-
type and HVA Ca2þ channel expressed in MPG neurons
at 10 lM concentration, as shown in Table 2. On the
other hand, compound 8a (KYS05001) bearing simple
benzylamide exhibited the higher selectivity for LVA T-
type over HVA Ca2þ channel, although its IC50 value
(0.9 lM) was similar to that of mibefradil (0.84 lM).
More importantly, all compounds (8a, 8d, 9, 10a, and
10b) did not exhibit Naþ channel blocking effect in
MPG neurons (the data were not shown) and also had
no cytotoxicities on HEK293 cells at 10 lM concentra-
tion as confirmed using MTT assay method (the data
were not shown). Therefore, it is likely that compound
8a (KYS05001) would be regarded as a new potent and
selective T-type Ca2þ channel blocker based on these
biological data.
Compared with the parent compound 8d, the current
inhibition by the reduced compound 9 was decreased in
both Xenopus oocytes (66.8% inhibition) and HEK293
cells (43.5 4.5% inhibition). The IC50 value (14.4 lM)
for the compound 9 was also higher than that of com-
pound 8d (2.5 lM). In the meanwhile, compound 10a
(KYS05041) and compound 10b (KYS05042) showed
increased potencies, and were 3.4- and 4.2-fold more
potent (IC50 ¼ 0.25 and 0.20 lM, respectively) than
mibefradil (IC50 ¼ 0.84 lM).
Table 2. The inhibitory activities and selectivity data for some 3,4-dihydroquinazolines
Compound
Structure
Xenopus oocyte
(a1H
HEK293 cells (a1G
)
MPG neuron assay
(% inhibition; 10 lM)
)
% Inhibition
(100 lM)
% Inhibition
(10 lM)a
IC50 (lM)b
LVA (T-type)
HVA (N-type)
O
N
H
8a (KYS05001)
8d (KYS05034)
77.0
91.9
90.1 2.3
0.90
76.0c
12.0c
N
N
N
O
N
H
92.3 1.3
2.50
37.7
32.2
O2N
N
N
N
N
O
N
H
9 (KYS05040)
66.8
43.5 4.5
14.40
4.7
18.4
H2N
N
N
O
N
H
O
O
S
10a
(KYS05041)
N
H
N
84.7
80.5
89.9 1.3
0.25
0.20
29.0
49.6
38.7
50.8
H3C
N
N
O
N
H
O
S
O
10b
(KYS05042)
89.0 2.3
N
N
H
F
N
N
a % Inhibition value ( SEM) was obtained by repeated procedures ðn P 3Þ.
b IC50 value was determined from the dose–response curve.
c The values were obtained at 50 lg/mL concentration.

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Y. S. Lee et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3379–3384
22. (a) Molina, P.; Aller, E.; Lorenzo, A. Synthesis 1998, 283;
(b) Saito, T.; Tsuda, K.; Saito, Y. Tetrahedron Lett. 1996,
37, 209.
In summary, 3,4-dihydroquinazoline derivatives as
novel scaffolds for nonpeptic T-type Ca2þ channel
blocker were prepared and evaluated for the blocking
effects against two isoforms of T-type Ca2þ channel sub-
family. Among them, compound 8a (KYS05001) has a
great potential as chemical platform for the future
development of useful pharmacophores without the side
effects resulting from nonselective blocking on HVA
Ca2þ channels and other types of ion channels.
23. (a) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992,
48, 1353; (b) Larksarp, C.; Alper, H. J. Org. Chem. 1998,
63, 6229; (c) Palomo, C.; Mestres, R. Synthesis 1981, 373.
24. Wang, F.; Hauske, J. R. Tetrahedron Lett. 1997, 38, 8651.
25. (a) Gaucher, A.; Zuliani, Y.; Cabaret, D.; Wakselman, M.;
Mazaleyrat, J.-P. Tetrahedron: Asymmetry 2001, 12, 2571;
(b) Dhaon, M. K.; Olesen, R. K.; Ramasamy, K. J. Org.
Chem. 1982, 47, 1962.
26. Lee, J.-H.; Gomora, J. C.; Cribbs, L. L.; Perez-Reyes, E. J.
Biophys. 1999, 77, 3034.
27. Monteil, A.; Chemin, J.; Bourinet, E.; Mennessier, G.;
Lory, P.; Nargeot, J. J. Biol. Chem. 2000, 275, 6090.
28. Compound 6d was obtained from our previous work. See:
Lee, B. H.; Lee, J. Y.; Chung, B. Y.; Lee, Y. S.
Heterocycles 2004, 63, 95.
29. Lee, J.-H.; Kim, E.-G.; Park, B. G.; Kim, K. H.; Cha,
S. K.; Kong, I. D.; Lee, J. W.; Jeong, S. W. J.
Neurophysiol. 2002, 87, 2844.
Acknowledgements
This study was supported by Vision 21 Program from
Korea Institute of Science and Technology (2E18000-
04-024).
30. Spectra data of selected compounds, 8a (KYS05001): mp
168 °C; 1H NMR (300 MHz, CDCl3) d 7.71 (br, 1H, –CO–
NH–CH2–Ph), 7.35–7.31 (m, 2H, aromatic), 7.29–7.19 (m,
5H, aromatic), 7.16–7.03 (m, 5H, aromatic), 6.96–6.92 (m,
2H, aromatic), 5.18 (dd, J ¼ 5:0 and 10.1 Hz, 1H, –CH2–
CH–N–), 4.53 (dd, J ¼ 6:0 and 14.4 Hz, 1H, –NH–CH2–
Ph), 4.42 (dd, J ¼ 6:3 and 14.4 Hz, 1H, –NH–CH2–Ph),
3.17 (br, 4H, piperidinyl), 2.68 (dd, J ¼ 10.1 and 14.0 Hz,
1H, –CO–CH2–), 2.23 (dd, J ¼ 5:0 and 14.1 Hz, 1H, –CO–
CH2–), 1.37–1.33 (m, 2H, piperidinyl), 1.18 (br, 4H,
piperidinyl); 13C NMR (75 MHz, CDCl3) d 170.4, 153.9,
146.1, 143.2, 138.6, 129.3, 128.8, 128.5, 128.4, 127.7, 127.0,
125.2, 124.9, 124.4, 123.2, 122.8, 122.3, 61.1, 47.4, 43.9,
41.9, 25.3, 24.7; HRMS (FAB, M+H) Calcd for
C28H31N4O 439.2498, found 439.2534; 10a (KYS05041);
1H NMR (300 MHz, CDCl3) d 7.66 (d, J ¼ 8:4 Hz, 1H,
aromatic), 7.58–7.73 (m, 3H, aromatic), 7.28–7.21 (m, 3H,
aromatic), 7.18–6.95 (m, 12H, aromatic), 5.19 (dd, J ¼ 5:2
and 10.1 Hz, 1H, –CH2–CH–N–), 4.35 (dd, J ¼ 6:1 and
14.2 Hz, 1H, –NH–CH2–), 4.24 (dd, J ¼ 5:5 and 14.8 Hz,
1H, –NH–CH2–), 3.28 (br, 4H, piperidinyl), 2.82 (dd,
J ¼ 10:5 and 14.4 Hz, 1H, –CO–CH2), 2.36 (dd, J ¼ 5:2
and 14.0 Hz, 1H, –CO–CH2–), 2.29 (s, 3H, –SO2–C4H4–
CH3), 1.33 (br, 2H, piperidinyl), 1.20 (br, 4H, piperidinyl);
13C NMR (75 MHz, CDCl3) d 170.4, 154.0, 144.9, 143.6,
138.9, 136.9, 136.7, 134.7, 129.8, 129.2, 129.0, 128.9, 127.3,
126.2, 125.9, 125,4, 124.4, 124.0, 121.1, 121.0, 61.7, 48.6,
43.2, 41.9, 24.8, 24.2, 21.7; HRMS (FAB, M+H) Calcd for
C35H38N5O3S 608.2695, found 608.2680; 10b (KYS05042);
1H NMR (300 MHz, CDCl3) d 7.66–7.62 (m, 2H, aro-
matic), 7.28–7.23 (m, 2H, aromatic), 7.20–7.06 (m, 9H,
aromatic), 7.04–6.90 (m, 4H, aromatic), 6.72 (br, 1H,
–CO–NH–CH2–), 5.19 (dd, J ¼ 6:0 and 9.9 Hz, 1H,
–CH2–CH–N–), 4.41 (dd, J ¼ 6:1 and 14.8 Hz, –NH–
CH2–), 4.24 (dd, J ¼ 5:5 and 14.8 Hz, –NH–CH2–), 3.28
(br, 4H, piperidinyl), 2.74 (dd, J ¼ 9:6 Hz and 14.1 Hz,
1H, –CO–CH2), 2.44 (dd, J ¼ 6:0 and 14.1 Hz, 1H, –CO–
CH2–), 1.39 (br, 2H, piperidinyl), 1.25 (br, 4H, piperid-
inyl); 13C NMR (75 MHz, CDCl3) d 170.1, 166.7, 153.9,
145.3, 141.7, 135.9, 135.0, 129.9, 129.7, 129.3, 128.9, 128.4,
126.7, 125.2, 124.8, 123.2, 121.5, 116.3, 116.0, 61.4, 47.9,
43.3, 42.0, 25.2, 24.6; HRMS (FAB, M+H) Calcd for
C34H35FN5O3S 612.2445, found 612.2436.
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