Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent T-type calcium channel antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.07.010

The discovery and synthesis of 4,4-disubstituted quinazolinones as T-type calcium channel antagonists is reported. Based on lead compounds 2 and 3, a focused SAR campaign driven by the optimization of potency, metabolic stability, and pharmacokinetic profile identified 45 as a potent T-type Ca²⁺ channel antagonist with minimized PXR activation. In vivo, 45 suppressed seizure frequency in a rat model of absence epilepsy and showed significant alterations of sleep architecture after oral dosing to rats as measured by EEG.

Full text of DOI:10.1016/j.bmcl.2010.07.010

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5147–5152
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent
T-type calcium channel antagonists
a
a
a
a
Kelly-Ann S. Schlegel a, , Zhi-Qiang Yang , Thomas S. Reger , Youheng Shu , Rowena Cube ,
Kenneth E. Rittle a, Phung Bondiskey a, Mark G. Bock a, George D. Hartman a, Cuyue Tang b, Jeanine Ballard b,
Yuhsin Kuo b, Thomayant Prueksaritanont b, Cindy E. Nuss c, Scott M. Doran c, Steven V. Fox c,
Susan L. Garson c, Richard L. Kraus c, Yuxing Li c, Victor N. Uebele c, John J. Renger c, James C. Barrow a
*
a Department of Medicinal Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486, USA
b Department of Drug Metabolism and Pharmacokinetics, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486, USA
c Department of Depression and Circadian Disorders, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The discovery and synthesis of 4,4-disubstituted quinazolinones as T-type calcium channel antagonists is
reported. Based on lead compounds 2 and 3, a focused SAR campaign driven by the optimization of
potency, metabolic stability, and pharmacokinetic profile identified 45 as a potent T-type Ca2+ channel
antagonist with minimized PXR activation. In vivo, 45 suppressed seizure frequency in a rat model of
absence epilepsy and showed significant alterations of sleep architecture after oral dosing to rats as mea-
sured by EEG.
Received 11 May 2010
Revised 2 July 2010
Accepted 6 July 2010
Available online 8 July 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Quinazolin-2-ones
Calcium channel antagonists
T-Type calcium channel
Epilepsy
Voltage-gated calcium channels play an important role in many
physiological processes.1,2 The Cav3.x family or T-type calcium
channels are one class of voltage-gated calcium channels being tar-
geted for the treatment of peripheral and central nervous system
(CNS) disorders. T-Type Ca2+ channels are classified into three cat-
strated in vivo efficacy in epilepsy and tremor models without
significant cardiovascular effects.15,16 We sought to identify a novel
series of selective T-type Ca2+ channel antagonists and demon-
strate their in vitro and in vivo activity for the treatment of CNS
disorders.
egories: Cav3.1 (
a
1G), Cav3.2 (
a
1H), and Cav3.3 (
a
1I). The
a
1G and
1H
Recently we reported a novel class of potent and selective T-
type calcium channel antagonists identified via an HTS campaign
based on the quinazolinone core as shown in Figure 1.17 This class
of quinazolinones was originally prepared as non-nucleoside re-
verse transcriptase inhibitors (NNRTI). Since this core has been
extensively studied, its chemical and physical properties were rel-
atively well known, making it an attractive lead.18 The in vitro po-
tency of compound 1 as shown in Figure 1 was determined via two
primary screening assays, the hyperpolarized and depolarized
FLIPR assay.19 Optimization of 1 led to the identification of quinaz-
olinones 2 and 3 as previously disclosed.17 Herein, we expand on
the SAR and discuss the in vivo and in vitro profiles of additional
compounds in this series.
We determined that the trifluoroethyl group was optimal at the
3-position based on its potency and metabolically robust nat-
ure.17,18 This knowledge allowed for a focused SAR campaign of
the 4-position. Various 6-chloro, 4,4-disubstituted quinazolinones,
where R1 and R2 are alkyl or aryl, were prepared via previously re-
ported methods17,18 as shown in Scheme 1. Utilizing a hydroxyl or
halogen handle, modification of the aryl substituent was
a
1I subunits are expressed primarily in the brain, while the
a
subunit has a broader and more peripheral expression.3 The vast
distribution of the T-type Ca2+ channels makes them a potential
target for the treatment of a number of CNS disorders including
sleep,4,5 epilepsy,6 schizophrenia,7 and pain.8 In the brain, T-type
Ca2+ channels are highly expressed in the cortex and thalamus,
where they play an important role in the proper functioning of
thalamocortical signalling.9,10
In the late 1990s, mibefradil was identified as the first T-type
Ca2+ channel antagonist for the treatment of hypertension.11
Although it is reported to be selective for the T-type channels,12,13
the outcomes of additional in vivo studies suggested reason for
caution when interpreting its effects.14 Despite these findings,
mibefradil is still used as the prototypical T-type antagonist. Earlier
reports from our laboratories identified a series of piperidine-de-
rived, selective T-type calcium channel antagonists that demon-
* Corresponding author. Tel.: +1 215 652 2888; fax: +1 215 652 3971.
E-mail address: kelly_ann_bieber@merck.com (K.-A. S. Schlegel).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.010

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K.-A. S. Schlegel et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5147–5152
N
F
CH3
CH3
CH3
F
Cl
F
F
Cl
4
N
Cl
F
6
N
N
F
F
O
N
H
O
N
N
H
O
H
1
2 (TTA-Q5)
3 (TTA-Q6)
α1i FLIPR IP Hyperpolarized
α1i FLIPR IP Depolarized
2172 nM
847 nM
239 nM
61 nM
590 nM
14 nM
Figure 1. T-Type calcium channel antagonists.
R1
R1
Cl
R2
N
R1
R1
OH
N
O
F
F
F
F
Cl
F
Cl
F
c, d
Cl
a, b
O
NH
F
F
F
N
H
O
N
H
O
NH2
O
N
H
4
5
6
7
Scheme 1. Reagents and conditions: (a) CDI, CH2Cl2, 45 °C; (b) NH2CH2CF3, THF, 50 °C; (c) Et3N, SOCl2, THF, ꢀ5 °C; (d) R2MgBr, THF, ꢀ5 °C.
performed via cross-coupling or displacement chemistry as shown
in Scheme 2.
like previous reports,17 the mixture did not proceed directly to
product 17 via the procedure of Magnus et al.20 In this series, the
mixture was refluxed in THF in the presence of triethylamine.
The reaction mixture was then cooled to ꢀ78 °C, and thionyl chlo-
ride was added, followed by the appropriate Grignard reagent to
afford the 5,6-difluoro, 4,4-disubstituted quinazolinone 17.21
Quinazolinones were screened for potency via depolarized and
hyperpolarized FLIPR assays as previously described.19 Because of
the state-dependent nature of these quinazolinone-type inhibi-
tors,17 the depolarized FLIPR assay became the primary screening
assay as this assay proved to be the best overall predictor of
in vivo activity. Structure–activity relationships for the 4-position
are shown in Table 1 (compounds 18–25). It is important to note
that the synthetic route provides racemic quinazolinones. Race-
mates showing activity in the FLIPR assay were subjected to reso-
lution by chiral HPLC, and the enantiomers were tested
individually. As demonstrated by 18 and 19, when both R4 and
Incorporation of fluorine atoms on the alkyl substituent is
shown in Scheme 3. The addition of allyl magnesium bromide
leads to the formation of quinazolinone 10. Subsequent ozonolysis
provides aldehyde 11 which can be directly treated with DAST to
produce compound 12. Alternatively, 11 can be reduced to the pri-
mary alcohol and then treated with DAST to yield compound 13.
A variety of halogen substitution patterns on the quinazolinone
core were explored, and some of these compounds can be prepared
via synthetic methods analogous to those reported for NNRTI18 and
TTA-Q5 and Q6.17 However, when fluorine atoms were incorpo-
rated at both the 5- and 6-positions, it was not possible to prepare
4,4-disubstituted quinazolinones as previously reported. Alternate
conditions are given in Scheme 4. The amino benzophenone 14
was treated with base and triphosgene followed by the addition
of 2,2,2-trifluoroethyl amine producing a mixture of 15 and 16. Un-
X
R
CH3
F
CH3
F
Cl
F
Reactant
Cl
F
N
N
F
F
N
O
N
H
O
H
8
9
Scheme 2. Reagents and conditions:
X
Reactant
R
Catalyst
Base
Solvent
—
Dioxane
Dioxane
DMSO
Temp (°C)
Time (min)
O
2-Fluoropyridine
Ar–B(OH)2
Ar–Sn(Bu)3
O-2-Pyr
Ar
Ar
—
Cs2CO3
K3PO4
—
130
150
150
150
30
30
30
30
Br
Br
Br
P(Cy)3, Pd2dba3
Pd(PPh3)4
CuI, proline
Morpholine
Morpholine
K2CO3

K.-A. S. Schlegel et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5147–5152
5149
F
F
F
F
F
Cl
F
N
F
F
b
O
N
N
O
H
24 %
a
12
F
F
F
F
Cl
F
Cl
F
N
99 %
F
c, b
F
N
H
O
N
H
O
96%, 26 %
11
10
F
F
Cl
F
N
N
H
O
13
Scheme 3. Reagents and conditions: (a) (1) ozone, MeOH, ꢀ78 °C; (2) dimethyl sulfide, ꢀ78 °C to rt; (b) DAST, 0 °C, CH2Cl2; (c) NaBH4, MeOH, 0 °C to rt.
F
Ar
F
F
F
F
Ar
OH
N
R
Ar
Ar
O
F
F
F
F
b, c, d
a
F
F
F
F
F
N
O
NH
F
F
F
N
O
N
O
NH2
H
H
O
N
H
14
15
16
17
Scheme 4. Reagents and conditions: (a) triphosgene, Et3N, CF3CH2NH2, ether, 0 °C to rt; (b) Et3N, THF, 80 °C, 1 h; (c) SOCl2, THF, ꢀ78 °C; (d) RMgBr, THF, ꢀ78 °C.
0
R4 are alkyl, lower activity in the FLIPR assay is observed. En-
interactions.22,23 As a way to mitigate PXR activation, the halogen
substituent and substitution pattern on the quinazolinone core
were explored as shown in Table 2. Incorporation of a fluorine
atom at the 5-position in conjunction with the 6-chloro substituent
(compound 32) showed a decrease in FLIPR potency. Removal of
the 6-chloro substituent coupled with the incorporation of a 5-flu-
oro (33) or 5,8-difluoro (34) substituent showed a decrease in
FLIPR potency and an increase in PXR activation. Replacement of
the 6-chloro substituent with a fluorine atom as in 35A provided
comparable FLIPR potency and PXR activation with TTA-Q5. In con-
trast, its enantiomer 35B showed decreased FLIPR potency. A 5,6-
difluoro substituent as in 36A maintained good FLIPR potency
and showed a decreased propensity for PXR activation when com-
pared to TTA-Q5. The 6-fluoro and 5,6-difluoro substitution pat-
terns exemplified by 35A and 36A were chosen for further SAR
studies.
In the 6-chloro quinazolinone series, FLIPR potency was greatly
dependent upon the composition of the 4-aryl and 4-alkyl substit-
uents. This trend is also observed in the 6-fluoro and 5,6-difluoro
quinazolinone series as shown in Table 3. Introduction of the n-
propyl group as in 37 provides a boost in FLIPR potency. Incorpora-
tion of a bulky t-butyl group in 38 or a polar group in 42 and 43 as
the 4-alkyl substituent is not well tolerated and caused a decrease
in FLIPR potency. The previously identified 4-fluorophenyl and
ethyl substituents employed in TTA-Q5 provided an increase in
FLIPR potency and a modest reduction of PXR activation in both
our 6-fluoro and 5,6-difluoro quinazolinone series (39 and 40). A
slightly longer alkyl chain (n-propyl) as in 41 also provided an in-
crease in FLIPR potency.
0
hanced potency is achieved when R4 = aryl and R4 = a small alkyl
group as exemplified in 21A. Compounds 21A and 21B are single
enantiomers with a >50-fold difference in FLIPR activity, which is
typical for quinazolinone isomers. Absolute configurations were
not determined, but the active isomer is assumed to be similar to
2 and 3 which were previously established.17
SAR of the aryl substituent was further explored via the incor-
poration of substituents in the 3- and 4-positions as shown in Ta-
ble 1 (examples 22 through 29). Incorporation of a methoxy
substituent in the 3- or 4-position was not well tolerated. The 4-
fluorophenyl group provided the best activity as measured by the
FLIPR assay where the active enantiomer 24A demonstrated a po-
tency of 25 nM. The 3,4-difluorophenyl substituent in 25 shows de-
creased potency. Further SAR of the 3-position was explored via
the incorporation of heterocycles as shown in examples 26 through
29. These heterocyclic derivatives exhibited potency in the FLIPR
assay and enhanced physical properties due to their increased
polarity.
A small alkyl substituent such as ethyl, propyl, or cyclopropyl as
one of the groups at the quinazolinone 4-position yields optimal
FLIPR potency; however, these alkyl groups were identified as a
metabolic liability. To block a potential metabolic site, fluoroalk-
anes 30A, 30B, 31A and 31B were prepared. While 30A and 31A
show reasonable potency in our FLIPR assay, they did not signifi-
cantly improve the potency of TTA-Q5 (61 nM).
While TTA-Q5 (2) showed good potency, selectivity, and vivo
efficacy,17 it was a pregnane X receptor (PXR) activator as were
many compounds in the 6-chloro quinazolinone series. TTA-Q5
showed PXR activation of 63% compared to the positive control Rif-
Metabolic stability became an issue with the 6-fluoro and 5,6-
difluoro quinazolinone series. When 40 was incubated with human
liver microsomes, less than 1% of compound remained after
ampicin at 10
lM. PXR is a potential liability as it could lead to
CYP3A4 activation; therefore, causing undesirable drug–drug

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K.-A. S. Schlegel et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5147–5152
Table 1
Table 2
SAR of the 4-position
SAR of 5-,6- and 8-positions
R4'
N
R4
F
F
Cl
R5
F
CH3
N
O
F
R6
H
4
0
N
Example R4
R4
a1I FLIPR IP depolarized
F
(nM)a
F
N
H
O
18
19
Cyclopropyl
Cyclopropyl
n-Butyl
sec-
Butyl
Allyl
Ethyl
111 30
447 66
R8
Example R5 R6 R8
a
1I FLIPR IP depolarized
PXR (% Rif at
20
Phenyl
Phenyl
Phenyl
4-Methoxy phenyl
3-Methoxy phenyl
4-Fluorophenyl
4-Fluorophenyl
3,4-Difluorophenyl
87 12
71 29
3885 1024
879 438
171 54
25 11
(nM)a
10 l
M)b
21A
21B
22
Ethyl
32
33
34
35A
35B
36A
36B
F
F
F
H
H
F
Cl
H
H
F
H
H
F
H
H
H
H
132 38
61
83
91
63
74
48
n-Propyl
n-Propyl
n-Propyl
n-Propyl
Ethyl
111 17
657 294
50 29
23
24A
24B
25
1317
141 43
F
F
3739c
20
2039c
2
F
F
NDd
O
a
All values are the mean the standard deviation of at least n = 3 measurements.
N
N
26
27
n-Propyl
n-propyl
73 33
Assay described in Ref. 19.
b
See Ref. 24.
Indicates single data point.
Not determined.
c
d
N
318 119
Table 3
4-Position SAR of 6-fluoro and 5,6-difluoro quinazolinones
R5
R4'
N
R4
S
N
F
F
F
F
28
29
n-Propyl
n-Propyl
62 29
N
H
O
Example
R4
R4’
R5
a
1I FLIPR IP
PXR (% Rif
O
N
depolarized
at 10 l
M)b
161 60
(nM)a
37
38
Phenyl
Phenyl
n-Propyl
t-Butyl
Ethyl
Ethyl
n-Propyl
Nitrile
CH2CH2OH
CH2CH2F
CH2CHF2
H
H
H
F
F
F
F
F
F
38 24
757 376
25 13
49
44
58
52
30A
30B
31A
31B
4-Fluorophenyl
4-Fluorophenyl
4-Fluorophenyl
4-Fluorophenyl
CH2CH2F
CH2CH2F
CH2CHF2
CH2CHF2
42 15
905b
39c
40c
41c
42
4-Fluorophenyl
4-Fluorophenyl
4-Fluorophenyl
4-Fluorophenyl
4-Fluorophenyl
4-Fluorophenyl
4-Fluorophenyl
60 12
16
9
6
4
469b
73
290 46
3089 284
NDd
NDd
53
a
All values are the mean the standard deviation of at least n = 3 measurements.
Assay described in Ref. 19.
43
44c
45c
17
14
4
8
b
Indicates single data point.
35
a
All values are the mean the standard deviation of at least n = 3 measurements.
60 min.25 The ethyl chain was identified as the primary metabolic
site. To block metabolism, the fluoroalkanes employed in the
6-chloroquinazolinone series were prepared. The monofluoroethyl
derivative (44, a single enantiomer) improved potency, maintained
lower propensity for PXR activation, and improved stability in hu-
man liver microsomes (66 2% remaining at 60 min). When a
difluoroethyl group is installed at the 4-position (45, a single enan-
tiomer26), potency is improved to 14 nM, PXR activation is reduced
(35%), and metabolic stability is improved (68 9% at 60 min). The
FLIPR potency was confirmed by whole cell patch clamp recording
at two holding potentials, ꢀ100 mV and ꢀ80 mV, and 45 showed
potencies of 190 nM and 31 nM, respectively.
The pharmacokinetic profile of 45 is shown in Table 5. Com-
pound 45 shows a reasonable pharmacokinetic profile across three
species, with t1/2 between 1 and 6 h, but exhibits modest bioavail-
ability in rat and monkey. Compound 45 is not an inhibitor of any
major CYPs, nor is it a time-dependent inhibitor of CYP3A4. It is not
a P-gp substrate in human (BA/AB ratio = 1.2) or rat (BA/AB ra-
tio = 1.5).27 The plasma protein binding was determined to be
98.5% in human and 97.9% in rat.
Assay described in reference 19.
b
See Ref. 24.
Indicates active enantiomer.
ND = not determined.
c
d
To further probe the SAR of the quinazolinone series, substitu-
tion at the 1-position of the quinazolinone core was explored.
Compounds were prepared by treatment of the quinazolinone core
with base followed by the addition of an alkyl halide or acid chlo-
ride. A representative subset of these compounds is shown in Table
4. Many structural changes are not tolerated and result in a de-
crease in potency as in 47 and 48 or an increase in PXR activation
as in 46. The incorporation of the methyl 4-pyridyl N-oxide moiety
maintained potency while decreasing PXR activation as in exam-
ples 49 and 50; however, these two compounds showed poor met-
abolic stability in human liver microsomes with only 3.8 1% and
18 3% remaining after 30 min, respectively. Incorporation of a
monofluoroethyl substituent at the 4-position in combination with
the methyl 4-pyridyl N-oxide substituent in the 1-position (51)
produced a potent (38 nM) compound with reasonable metabolic

K.-A. S. Schlegel et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5147–5152
5151
Table 4
1-Position SAR of 5,6-difluoro-4,4-disubstituted quinazolinones
R4'
N
F
R4
R4'
N
F
R4
F
F
F
F
F
F
F
F
N
O
N
O
R1
H
0
Example
R4
R4
R1
a
1I FLIPR IP
PXR (% Rif
at 10
depolarized (nM)a
l
M)b
46c
4-Fluorophenyl
4-Fluorophenyl
Ethyl
Ethyl
CH2CH2OCH3
53 26
70
N
O
47c
1833 460
NDd
48c
49c
4-Fluorophenyl
4-Fluorophenyl
Ethyl
Ethyl
127 12
NDd
N
O
O
12
6
4
1
5
26
+
N
–
O
50c
51c
4-Fluorophenyl
4-Fluorophenyl
n-Propyl
11
56
+
N
–
O
CH2CH2F
38
+
N
–
O
a
b
c
All values are the mean the standard deviation of at least n = 3 measurements. Assay described in Ref. 19.
See Ref. 24.
Indicates active enantiomer.
ND = not determined.
d
Because of the involvement of T-type Ca2+ channels in the thala-
mocortical network that is believed to play a role in these seizures,
EEG measurement of seizure suppression in WAG/Rij rats can be
interpreted as T-type Ca2+ channel inhibition. A 3 mg/kg oral dose
of 45 to WAG/Rij rats resulted in a 44% inhibition of total seizure
time at 4 hours post dose. An inhibition of 70% is observed with
a 10 mg/kg oral dose of 45 at 4 h post dose.
Table 5
Pharmacokinetic profiles
Species
CLp (mL/min/kg)
t1/2 (h)
Vdss (L/kg)
F (%)
Pharmacokinetic profile of 45
Rat
55
1.6
5.9
5.8
6.7
3.6
9.8
15
15
Dog
Monkey
10.5
23
Pharmacokinetic profile of 49
To evaluate the effects of a T-type calcium channel antagonist
on vigilance, 45 was dosed in a seven day crossover rat study. In
this study, electrocorticogram (ECoG) and electromyogram (EMG)
signals were measured in rats and scored for the time spent awake,
in light sleep, delta sleep, or REM. The rats received a 10 mg/kg oral
dose of 45 30 min prior to their inactive (sleep) phase. As shown in
Figure 2, a decrease in active wake and REM and an increase in del-
ta sleep are observed immediately post dose. These effects per-
Rat
21
1.1
1.3
1.7
0.37
22
Dog
3.5
stability (59 3% remaining after 60 min); however, it became a
PXR activator.
Compound 49 (single, active enantiomer) was more fully pro-
filed and showed moderate clearance and short half-life in rat
and dog as shown in Table 5. Although 49 had lower plasma pro-
tein binding (89% bound), it was a P-gp substrate in rat (BA/AB
ratio = 7).
On the strength of its potency, relative metabolic stability, and
reduced PXR activation, the efficacy of compound 45 was evalu-
ated in our primary in vivo screening model of absence epilepsy.
This model uses Wistar Albino Glaxo rats bred in Rijswijk, The
Netherlands (WAG/Rij), which display EEG patterns and behaviors
typical of epileptic conditions, including excessive seizures.28
sisted for up to 3 h. During this study an exposure of 6
lMꢁh was
reached, resulting in the observed robust effect on sleep architec-
ture. The effect of other selective T-type Ca2+ channel antagonists
such as TTA-Q6 and other quinazolinones,17 piperidine-derived
analogs,15,16 and TTA-A229 on rat sleep have been previously re-
ported. All show results similar to those observed for 45 providing
further evidence for the involvement of T-type calcium channels in
vigilance state maintenance.
In conclusion, the SAR of the quinazolinone series was explored
and optimized on the basis of T-type Ca2+ channel potency, PXR

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23. Based on Ref. 22 and in house data, the following guidelines are used to
determine the potential for clinical drug–drug interactions. Using % activation
(compared to the positive control Rifampin), the criteria for having a high
potential for clinical drug–drug interaction is defined as a value of >40%,
between 15% and 40% for moderate potential, and <15% as having a low
potential.
Figure 2. Effect of 45 (single, active enantiomer) on n = 7 male rat for active, light,
delta, and REM sleep for 16 h after dosing 10 mg/kg PO. Data is average minutes of
active wake, light sleep, delta sleep, or REM in each 30 min bins ( SEM) starting at
dose time (abscissa 15:00). Significance at each time point reported as tick marks
(short = p <0.05, medium = p <0.01, long = p <0.001) and gray vertical lines through
significantly different comparisons based on a linear mixed effects ANOVA at each
time point.
activation, metabolic stability and pharmacokinetic profile. The
tractable SAR of the quinazolinone series led to the discovery of po-
tent T-type Ca2+ channel antagonist 45, which suppressed seizure
activity in the WAG/Rij model and altered the sleep architecture
of rats. These findings suggest that T-type Ca2+ channel antagonists
could potentially be used for the treatment of a number of CNS
disorders.
Acknowledgments
24. Gao, Y. D.; Olson, S. H.; Balkovec, J. M.; Zhu, Y.; Royo, I.; Yabut, J.; Evers, R.; Tan,
E. Y.; Tang, W.; Hartley, D. P.; Mosley, R. T. Xenobiotica 2007, 37, 124.
25. For metabolic stability assay, compounds (1 lM) were incubated with human
liver microsomes (0.2 mg protein/mL) in the presence of NADPH cofactor for 30
or 60 min at 37 °C.
26. Compound 45 is a single, active enantiomer. All in vitro and in vivo data
included for 45 was collected on the active enantiomer.
27. Hochman, J. H.; Pudvah, N.; Qiu, J.; Yamazaki, M.; Tang, C.; Lin, J. H.;
Prueksaritanont, T. Pharm. Res. 2004, 21, 1686–1691.
The authors thank Nicole Pudvah for PGP measurements, Ken
Anderson, Leslie Geer, and Debra McLoughlin for PK analysis,
Charles Ross and Joan Murphy for high resolution mass spectral
analysis, and Carl Homnick, ZhiQiang Wang, and Todd Anderson
for chiral separations.
References and notes
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