Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.11.045

A 5,7-dichloro-3-phenyl-3-methyl-quinoline-2,4-dione (11a) has been identified in a random screen as a lead for 5-HT₆ antagonist. During the lead optimization process, several analogs were synthesized and their biological activities were investigated. Within this series, several compounds display high binding affinity and selectivity for the 5-HT₆ receptor. In particular, 3-(4-hydroxyphenyl)-3-methyl-quinoline-2,4-dione (12f) exhibits high affinity (K_i = 12.3 nM) for 5-HT₆ receptor with good selectivity over other serotonin and dopamine (D₁-D₄) receptor subtypes. In a functional adenylyl cyclase stimulation assay, this compound exhibited considerable antagonistic activity (IC₅₀ = 0.61 μM).

Full text of DOI:10.1016/j.bmcl.2007.11.045

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 738–743
Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones
as a new class of selective 5-HT6 receptor antagonists
Churl Min Seong,a,* Woo Kyu Park,b Chul Min Park,a
Jae Yang Kongb and No Sang Parka
aCenter for Medicinal Chemistry, Drug Discovery Division, Korea Research Institute of Chemical Technology,
100 Chang-dong, Yuseong-gu, Daejeon 305-606, South Korea
bCenter for Drug Discovery Technologies, Drug Discovery Division, Korea Research Institute of Chemical Technology,
100 Chang-dong, Yuseong-gu, Daejeon 305-606, South Korea
Received 11 June 2007; revised 11 October 2007; accepted 13 November 2007
Available online 17 November 2007
Abstract—A 5,7-dichloro-3-phenyl-3-methyl-quinoline-2,4-dione (11a) has been identified in a random screen as a lead for 5-HT6
antagonist. During the lead optimization process, several analogs were synthesized and their biological activities were investigated.
Within this series, several compounds display high binding affinity and selectivity for the 5-HT6 receptor. In particular, 3-(4-
hydroxyphenyl)-3-methyl-quinoline-2,4-dione (12f) exhibits high affinity (Ki = 12.3 nM) for 5-HT6 receptor with good selectivity
over other serotonin and dopamine (D1–D4) receptor subtypes. In a functional adenylyl cyclase stimulation assay, this compound
exhibited considerable antagonistic activity (IC50 = 0.61 lM).
Ó 2007 Elsevier Ltd. All rights reserved.
The 5-HT6 receptor is the most recently discovered mem-
ber of the serotonin receptor family.1 It was isolated from
rat mRNA in 1993, found to consist of 438 amino acids
with seven transmembrane domains, and is positively
coupled to adenylyl cyclase.2 Human 5-HT6 receptor
was subsequently cloned in 1996 and shares 89% homol-
ogy with the rat receptors.3 Expression of the 5-HT6
receptor mRNA is localized exclusively in the central ner-
vous system (CNS).4 Binding studies have disclosed that
certain tricyclic antipsychotic drugs and antidepressants
have significant affinity for 5-HT6 receptor.5 The localiza-
tion and their affinity for the CNS drugs have sparked ef-
forts to elucidate their role in treatment of CNS disorders,
including schizophrenia and depression, and more recent
studies implicate possible involvement in cognition and
memory dysfunction.6–8 Most of the early exploration
of 5-HT6 pharmacology was largely dependent on the
use of nonselective agents. However, this lack of selectiv-
ity limited their value for most other pharmacological
studies. In more recent efforts several selective 5-HT6
antagonists have been reported including Ro 04-6790 (1,
Ki = 55 nM), Ro 63-0563 (2, Ki = 512 nM),9 SB-271046
(3, Ki = 1 nM),10 SB-357134 (4, Ki = 3 nM),11 and MS-
245 (5, Ki = 2.3 nM)12,13 as shown in Figure 1. Interest-
ingly, although these represented independent discover-
ies, the compounds were identified by random screening
methods and all possess a sulfonamide moiety. In contrast
to the above-mentioned sulfonamides or tryptamine
derivatives, Hoffmann-LaRoche (6, Ki = 1.0 nM)14 and
Pharmacia-Upjohn (7, Ki = 1.4 nM)15 also revealed sev-
eral aromatic sulfones.
Advent of these selective agents has greatly benefited 5-
HT6 studies, and this field of research has experienced
resurgence. Despite the high affinity and selectivity of
these compounds, a significant problem in preclinical
trials was their poor penetration to cross the blood brain
barrier. Newer agents are aimed at improving pharma-
cokinetic and pharmacodynamic properties.
The purpose of our present study was to identify novel,
potent antagonists with enhanced selectivity for 5-HT6
receptors that might be useful as potential therapeutics
with improved brain-penetrating properties. We began
our investigation by exploring the structure–affinity rela-
tionships for the known 5-HT6 receptor antagonists and
Keywords: 5-HT6 Receptor antagonist; Schizophrenia; Alzheimer’s
disease; Quinoline-2,4-dione.
*
Corresponding author. Tel.: +82 42 860 7134; fax: +82 42 861
1291; e-mail: cmsung@krict.re.kr
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.045

C. M. Seong et al. / Bioorg. Med. Chem. Lett. 18 (2008) 738–743
739
Cl
NH2
H
N
Br
Br
H
N
H
N
H
N
O O
S
Me
S
N
O
O
H
N
N
X
N
F
N
S
H
S
HN
O
O
MeO
Me
MeO
3, SB-271046
4, SB-357134
1, X=N, Ro 04-6790
2, X= CH, Ro 63-0563
Me
N Me
CH3
NH
O
HN
O
O
N
Br
S
N
S
O
MeO
NH2
N
N
O
S
O
Ar
F
5, MS-245
7
6
Figure 1. Structures of 5-HT6 receptor antagonists.
high throughput screening with in-house compounds.
We found that (+/À)-5,7-dichloro-3-phenyl-3-methyl-
quinoline-2,4-dione (11a, Ki = 54.7 nM) exhibits good
affinity and significant selectivity for 5-HT6 receptor.
Our studies were then directed toward the structural
modification of quinoline-2,4-dione skeleton for the
O
COOMe
a,b
c, d
.
O
X
X
X
N
NH2
NH2
9
H
8
Scheme 1. Reagents and conditions: (a) Chloral hydrate, NH2OH–HCl, Na2SO4, H2O, reflux; (b) conc. H2SO4, 80 °C; (c) H2O2/aq.NaOH, rt; (d)
CH2N2/Et2O, rt.
O
Me
Me
Y
OH
O
a
b
X
Y
X
Y
O
N
H
N
H
O
Me
10
11 & 12
Scheme 2. Reagents and conditions: (a) SOCl2, CH2Cl2, then 9, reflux; (b) LiHMDS, THF, À78 °C to reflux.
Table 1. 5-HT6 receptor binding affinity of 3-methyl-3-phenyl quinoline-2,4-diones, 11a–ja
Compound
Substituents (X)
Kib (nM)
a
b
c
d
e
f
5,7-Cl2
54.7 14.4
>1000
>1000
5,6,7,8-H
7-Cl
6,7-Cl2
O
5
8
Me
3
>1000
196.9 57
>1000
6
5,7-Br2
6,8-Br2
4
1
X
7
N
O
2
g
h
i
5-Cl,7-OMe
5-Br,7-OMe
5,7-di-OMe
5-Cl,7-NMe2
344.6 46
73.2 12
728 115
715 110
H
11a~j
j
a Displacement of [3H]-LSD binding to cloned human 5-HT6 receptors expressed in HEK293 cell line.
b All values are means SEM of three separate competition experiments.

740
C. M. Seong et al. / Bioorg. Med. Chem. Lett. 18 (2008) 738–743
Table 2. 5-HT6 receptor binding affinity of 3-aryl-5,7-dichloro-3-
methyl quinoline-2,4-diones, 12a–qa
Table 2 (continued)
Compound
Ar
Kib (nM)
Cl
O
Me
Br
Ar
12q
77.5
OH
Cl
N
H
O
12a~q
a Displacement of [3H]-LSD binding to cloned human 5-HT6 receptors
expressed in HEK293 cell line.
b All values are means of three separate competition experiments.
Compound
Ar
Kib (nM)
11a
54.7
delineation of optimal substitution patterns. A series of
3-aryl-3-methyl-quinoline-2,4-diones were prepared and
their pharmacological profiles for 5-HT6 receptors were
examined. These compounds are structurally different
from prototypical antagonists in that they do not con-
tain a sulfonamide or a sulfone functionality, but rather
a substituted quinoline-2,4-dione skeleton. Herein, we
wish to report the synthesis and biological evaluation
of novel analogs of 11a.
12a
12b
12c
12d
12e
12f
12g
12h
12i
952
I
877
Cl
304
Br
OH
30.1
147
The general synthetic approach to 3,3-disubstituted
quinoline-2,4-diones is presented in Schemes 1 and 2.
The key intermediates for many of the quinoline-2,4-
dione derivatives are substituted anthranilic esters. The
anthranilic esters were either purchased or prepared
from the corresponding anilines.
OMe
OH
12.3
>1000
156
The substituted anilines were treated with chloral hy-
drate and hydroxylamine hydrochloride to produce the
N-(substituted phenyl)(hydroxylimino)acetamides which
were dehydrated in warmed concentrated sulfuric acid
to give the isatins 8.16 Oxidation with hydrogen peroxide
gave the substituted 2-amino-benzoic acid which was
converted to the corresponding methyl ester 9 by treat-
ment with ethereal diazomethane at room temperature.
The preparation of 3,3-disubstituted-quinoline-2,
4-diones was carried out by condensation of the
anthranilic methyl ester 9 with the appropriate 2-methyl-
2-phenyl propionic acids. The intermediate acid chloride
was prepared in situ by treatment of the acids with SOCl2
in anhydrous methylene chloride at room temperature.
NO2
NH2
257
NHMe
NMe2
NHEt
NEt2
12j
346
12k
12l
28.3
9.2
Coupling of the crude acid chloride with the anthranilic
methyl ester 9 was conducted under anhydrous condi-
tions to provide the corresponding amides 10. Treat-
ment of the amide 10 with LiHMDS [preparedin situ
using n-BuLi in THF at À78 °C] in THF or NaH in
DMF at elevated temperatures induced intramolecular
cyclization to give the target 3,3-disubstituted quino-
line-2,4-diones 11 and 12 in good yields.
OBn
12m
82.4
NO2
12n
12o
12p
>1000
>1000
>1000
The affinities of the synthesized compounds for the hu-
man recombinant 5-HT6 receptor expressed by
HEK293 cell line were determined using [3H]-lysergic
acid diethylamide (LSD).17 The results are summarized
in Table 1. All compounds were tested as the racemates.
The 3-methyl-3-phenyl-quinoline-2,4-dione (11a) as a
hit compound in a random screen demonstrated reason-
ably high binding affinity (Ki = 54.7 nM) to 5-HT6
receptor. This implies that the sulfonamide backbone
separated from a basic amine by an aryl group in well-
OMe
NO2
OH
Br
OBn

C. M. Seong et al. / Bioorg. Med. Chem. Lett. 18 (2008) 738–743
741
Cl
O
Me
O
OMe
Cl
N
H
(R)-12e
Figure 2. ORTEP representation of (R)-form isomer of 12e.
known antagonists such as SB-271046 or Ro 04-6790 is
not an essential requirement for binding to the 5-HT6
receptor and the substituted quinoline-2,4-diones could
be the alternative structure for new potent 5-HT6 recep-
tor ligand.
isomer (R)-12e (Ki = 893 nM) and its racemate 12e
(Ki = 563 nM). This implies (S)-configuration on C3 in
the quinolone nucleus is preferable in binding for 5-
HT6 receptor.
Compounds 11a, 12d, 12f, and 12m were examined fur-
ther for binding activity toward several serotonergic and
dopaminergic receptors (Table 3). The 5-HT6 receptor
selectivity of compounds 11a and 12f was greater than
200-fold over 5-HT1A, 5-HT2A, 5-HT2C, 5-HT7, and
dopamine (D1–D4) receptors and was comparable to
that of a reference compound SB-271046. Meanwhile,
compounds 12m produced moderate binding affinity
for the 5-HT1A and D1 receptors showing 0.17 and
0.12 lM of Ki values, respectively.
Additional analogs of compound 11a provided consis-
tent results to further support the hypothesis. The 5,7-
disubstituted analogs (11e and 11h) showed moderate
binding activities to 5-HT6 receptor, whereas the unsub-
stituted analog 11b did not exhibit any significant bind-
ing activity. Within this series, none of the analogs
showed better binding affinity compared to hit com-
pound 11a.
Next, we investigated the substituent effects on the phe-
nyl ring at the C3 position of quinolone nucleus with
remaining the 5,7-dichloro-substitution as shown in
Table 2.
The functional efficacy of compound 12f was evaluated
by measuring 5-HT-stimulated cAMP accumulation
using HeLa cell line expressing the cloned human 5-
HT6 receptor.19 In this study, 5-HT-stimulated cAMP
accumulation was significantly inhibited by compound
12f (IC50: 615 nM), indicating that compound 12f is a
selective and potent 5-HT6 receptor antagonist. Nonse-
lective antagonist methiothepin was also found to be
an antagonist showing 127 nM of IC50 value in the pres-
ent experiments.
A wide range of substituted 3-aryl-3-methyl-quinoline-
2,4-diones were prepared by parallel synthesis. In partic-
ular, compounds 12d, 12f, 12k, and 12l containing a
hydroxyl, ethylamino or diethylamino group gave high
binding affinities. In contrast, the binding activities of
compounds 12g, 12n and 12o containing the electron
withdrawing NO2 substituent were detrimental. Intro-
duction of halogen atom on C2-phenyl ring in com-
pounds 12a, 12b, and 12c was unfavorable in 5-HT6
receptor binding. To elucidate the optimal configuration
in binding for 5-HT6 receptor, each optically pure enan-
tiomer of 3-methyl-3-(4-methoxyphenyl-quinoline-2,4-
dione 12e was separated by a chiral chromatography
using Pirkle-type stationary phase.18 The absolute con-
figuration of each isomer was determined by X-ray anal-
ysis, as shown in Figure 2. (S)-isomer (S)-12e
(Ki = 293 nM) showed higher binding affinity than (R)-
In summary, 5,7-dichloro-3-methyl-3-phenyl-quinoline-
2,4-dione (11a) was isolated in high-throughput screen-
ing and represents a suitable template for the further
development of serotonin 5-HT6 receptor ligands. The
incorporation of appropriate substituents (e.g., 12d,
12f, 12k, and 12l) resulted in compounds with improved
affinity for the receptor. These compounds are notewor-
thy for their structural uniqueness and selectivity as 5-
HT6 receptor. Additional studies with such compounds
are now in progress.

742
C. M. Seong et al. / Bioorg. Med. Chem. Lett. 18 (2008) 738–743
Table 3. 5-HT6 Receptor selectivity profiles over serotonin (5-HT1A–5-HT7) and dopamine (D1–D4) receptor subtypea
Compounds
Kib (lM)
5-HT7
5-HT6
5-HT1A
5-HT2A
5-HT2C
D1
D2
D3
D4
11a
12f
0.054
0.012
0.082
0.030
0.0005
>10
>10
0.17
>10
0.34
>10
>10
0.72
>10
1.74
>10
>10
>10
>10
0.53
>10
>10
0.60
>10
0.26
>10
>10
0.12
1.81
0.12
>10
>10
>10
>10
0.46
>10
>10
>10
>10
1.33
>10
>10
>10
>10
0.13
12m
12d
SB-271046
a Receptors were all cloned human receptors expressed in CHO, HEK293 or SF9 cells, and [3H] radioligands were as follows; 8-OH-DPAT (5-HT1A),
ketanserin (5-HT2A), mesulergine (5-HT2C), LSD (5-HT6 & 5-HT7), SCH-23390 (D1), and spiperone (D2–D4).
b Ki values are means of two or three separate competition experiments.
H.; Riley, G.; Routledge, C.; Wyman, P. J. Med. Chem.
1999, 42, 202.
Acknowledgments
11. Bromidge, S. M.; Clarke, S. E.; Gager, T.; Griffith, K.;
Jeffrey, P.; Jennings, A. J.; Joiner, G. F.; King, F. D.;
Lovell, P. J.; Moss, S. F.; Newman, H.; Riley, G.; Rogers,
D.; Routledge, C.; Serafinowska, H.; Smith, D. R. Bioorg.
Med. Chem. Lett. 2001, 11, 55.
We thank Korea Tomorrow and Globalization.(KT&
G) Co., Ltd. for financial support. We also thank Dr.
You-Hui. Kim for helpful discussions.
12. Tsai, Y.; Dukat, M.; Slassi, A.; MacLean, N.; Demchy-
shyn, L.; Savage, J. E.; Roth, B. L.; Hufesein, S.; Lee, M.;
Glennon, R. A. Bioorg. Med. Chem. Lett. 2000, 10, 2295.
13. Russell, M. G.; Baker, R. J.; Barden, L.; Beer, M. S.;
Bristow, L.; Broughton, H. B.; Knowles, M.; McAllister,
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Levitan, I. B. J. Biol. Chem. 1980, 255, 6679; (c)
Membranes from stable HEK-293 cell line expressing the
human recombinant 5-HT6 serotonin receptor (Perkin-
Elmer Life and Analytical Sciences, Boston, USA) were
used. For the binding assay, aliquots of receptor mem-
branes, 1.6 nM [3H]LSD, and appropriate concentrations
of test compounds were added to 0.25 mL of 50 mM Tris–
HCl (pH 7.4) buffer containing 10 mM MgCl2 and 0.5 mM
EDTA. Incubations were carried out for 60 min at 37 °C,
and these were terminated by rapid filtration using an
Innotech cell harvester (Innotech Biosystems, Switzerland)
through Whatman GF/C glass fiber filter presoaked in 0.3%
polyethylenimine. The filter was covered with MeltiLex,
sealed in a sample bag followed by drying in the microwave
oven, and counted by MicroBeta Plus (Wallac, Finland).
Nonspecific binding was determined in the presence of
0.5 lM methiothepin. Competition binding studies were
carried out with 7–8 varied concentrations of the test
compounds run in duplicate tubes, and isotherms from
three assays were calculated by computerized nonlinear
regression analysis (GraphPad Prism Program, San Diego,
USA) to yield inhibition constant (Ki) values.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2007.11.045.
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C. M. Seong et al. / Bioorg. Med. Chem. Lett. 18 (2008) 738–743
743
(d, J = 8.9 Hz, 2H, ArH), 6.99–7.08 (m, 3H, ArH), 7.23 (d,
J = 1.9 Hz, 1H, ArH), 11.25 (s, 1H, NH); mp. 208–210 °C;
MS(EI) m/e 349[M+], 162, 134; HRMS m/e calcd for
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graphic data (excluding structure factors) for the structure
in this paper have been deposited with Cambridge
Crystallographic Data Center as supplementary publica-
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isobutylxanthine(IBMX). Incubation was started by addi-
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Following 20 min incubation at 37 °C, intracellular cAMP
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and a compound showing inhibitory effects on 5-HT-
stimulated cAMP accumulation was classified as an
antagonist.
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