Novel and potent 5-piperazinyl methyl- N1-aryl sulfonyl indole derivatives as 5-HT6 receptor ligands

Article abstract of DOI:10.1021/ml100101u

The exclusive distribution of 5-HT₆ receptors in the brain regions associated with learning and memory makes it an ideal target for cognitive disorders. A novel series of 5-piperazinyl methyl-N₁-aryl sulfonyl indoles were designed and synthesized as 5-HT₆R ligands. Most of the synthesized compounds are potent when tested by in vitro radioligand binding assay. The lead compound from the series does not have the CYP liabilities and is active in an animal model of cognition.

Full text of DOI:10.1021/ml100101u

pubs.acs.org/acsmedchemlett
Novel and Potent 5-Piperazinyl Methyl-N1-aryl Sulfonyl
Indole Derivatives as 5-HT6 Receptor Ligands
Ramakrishna V. S. Nirogi,*,† Prabhakar Kothmirkar,† Ramasastri Kambhampati,†
Jagadish Babu Konda,† Sobhanadri Arepalli,† Narasimhareddy G. Pamuleti,†
Amol D. Deshpande,† Trinathreddy Bandyala,† Anil K. Shinde,† and P. K. Dubey‡
†Discovery Research, Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034,
India, and ‡Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad
ABSTRACT The exclusive distribution of 5-HT6 receptors in the brain regions
associated with learning and memory makes it an ideal target for cognitive
disorders. A novel series of 5-piperazinyl methyl-N1-aryl sulfonyl indoles were
designed and synthesized as 5-HT6R ligands. Most of the synthesized compounds
are potent when tested by in vitro radioligand binding assay. The lead compound
from the series does not have the CYP liabilities and is active in an animal model of
cognition.
KEYWORDS 5-Piperazinyl methyl-N1-aryl sulfonyl indole, 5-HT6R, NORT, SAR,
Morris water mazes, PK profile
he 5-HT6 receptors (5-HT6R) are perceived by the
scientific community as possible targets for the treat-
ment of cognitive disorders as well as obesity.1-3
ated on the indole nucleus. Hence, we initiated research in
this direction and reported our initial findings on N1-aryl
sulfonyl indole-3-piperzinylmethyl series.23 The compounds
from this series (compounds I) are potent, safe, brain
penetrant, highly selective, and orally bioavailable 5-HT6R
antagonists. To further explore the structure-activity rela-
tionship (SAR) scope, the CH2 piperazinyl moiety in com-
pounds I was moved from the C3 of indole to the C5 of
indole. The details of the chemistry, SAR, and pharmacolo-
gical data presented over here are the subject matter of this
paper.
The synthesis of final compounds was carried out
as shown in Schemes 1-3. 4-Nitro-3-methyl benzoic
acid 1 was treated with thionylchloride and substitu-
ted piperazines to obtain the amide 2. The latter com-
pound, when treated with DMFDMA and pyrrolidine,24,25
gave the styrene derivative 3. The styrene derivative 3
underwent reductive cyclization, when treated with hy-
drazine hydrate and Raney Ni, to obtain 4. The inter-
mediate 4 was subsequently reduced to 5-piperazinyl
methyl indoles 5 with lithium aluminum hydride. The
intermediate 5 was then treated with various substituted
benzene sulfonylchlorides to obtain the title compounds
6 (Scheme 1).
T
Many pharmaceutical companies like Roche,4,5 GlaxoSmith-
Kline,6 Eli Lilly, Predix, Dr. Esteves lab, Wyeth, etc. have
patents covering diverse structures (Figure 1). Several
5-HT6R antagonists (SB-742457,7,8 SAM-531, and Lu
AE58054) have already entered9-15 phase II clinical trials
for the enhancement of cognitive function; PRX-0703416 is
projected for both obesity and cognition. Over a period of 5
years, we at Suven have designed and developed a number
of structurally diverse, potent, and selective 5-HT6R antago-
nists through classical medicinal chemistry and scaffold
hopping approaches. Our own internally developed com-
pound SUVN-502 has completed phase I clinical trials for
cognitive impairment in schizophrenia and Alzheimer's
disease.17
A general survey of the literature reveals that the reported
5-HT6R ligands18 have some major common features that
are apparent as the basic minimum pharmacophore, the
basic nitrogen, which could be the primary binding site at the
receptor aspartate residue, and two other aromatic sites,
which may be involved in the secondary binding (π-staking)
interactions with the receptor. In an effort to identify and
map the pharmacophoric requirements for the 5-HT6R
ligands, several diverse classes of compounds were taken
up for synthesis and evaluation. N1-aryl sulfonyl tryptamine
is one of the major classes of compounds reported as 5-HT6R
ligands.19-22
The following strategy was adopted to prepare com-
pounds 11 and 12 (Scheme 2). Indole 5-carboxaldehyde
724,25 was treated with NCS to obtain the 3-chloro indole
derivatives 8. The intermediate 8 was further reacted with
Interestingly, although a lot of work has already been
published on the effect of changes made in the nature of
the side chain of tryptamines,18 the alkyl piperazinyl or other
cyclic amino side chains were not much studied and evalu-
Received Date: May 7, 2010
Accepted Date: June 6, 2010
Published on Web Date: June 24, 2010
r
2010 American Chemical Society
340
DOI: 10.1021/ml100101u ACS Med. Chem. Lett. 2010, 1, 340–344
|

pubs.acs.org/acsmedchemlett
Scheme 2. Synthesis of 3-Chloro-5-piperazinyl Methyl-N1-aryl
Sulfonyl Indoles 12a
Figure 1. Reported 5-HT6R ligands.
a Reagents and conditions: (a) NCS, 1,4-dioxane, room temperature, 4 h.
(b) THF, KH, various substituted benzenesulfonyl chlorides, room
temperature, 4 h. (c) N-Boc-substituted piperazines, sodium triacetoxy
borohydride, EDC, room temperature, 8 h. (d) TFA, DCM, room tem-
perature, 2 h. (e) DMF, K2CO3, R-X (R = CH3 or C2H5, and X = I), room
temperature, 4 h.
Figure 2. Design of 5-piperazinyl methyl-N1-aryl sulfonyl indoles.
Scheme 1. Synthesis of 5-Piperazinyl Methyl-N1-aryl Sulfonyl
Indoles 6a
Scheme 3. Synthesis of 5-Piperazinyl Methyl-N1-aryl Carbonyl
and Benzyl Indoles 13a and 14a
a Reagents and conditions: (a) Thionylchloride, substituted pipera-
zines, THF, DMF, 10 °C to room temperature, 4 h. (b) DMFDMA, DMF,
pyrrolidine, 100-110 °C, 6 h. (c) Hydrazine hydrate, Raney Ni, THF,
MeOH, 70 °C, 5 h. (d) LAH, THF, 70 °C, 6 h. (e) THF, KH, various
substituted benzenesulfonylchlorides, room temperature, 3 h.
a Reagents and conditions: (a) Substituted piperazines, sodium triace-
toxy borohydride, EDC, room temperature, 8 h. (b) THF, KH, various
substituted benzoyl chlorides, room temperature, 4 h. (c) THF, KH,
various substituted benzyl chlorides, room temperature, 4 h.
various substituted benzenesulfonyl chlorides to obtain the
sulfonyl derivatives 9. The sulfonyl derivatives 9 when
treated with N-Boc piperazines under reductive amination
conditions gave the 5-piperazinyl methyl indole derivatives
10. Intermediate 10 was deprotected with trifluoro acetic
acid to obtain compound 11. Compound 11 was alkylated
r
2010 American Chemical Society
341
DOI: 10.1021/ml100101u ACS Med. Chem. Lett. 2010, 1, 340–344
|

pubs.acs.org/acsmedchemlett
Table 1. 5-HT6 Receptor Binding Data of Compounds IIa
with alkyl halide to yield the targeted N-alkylpiperazinyl
derivatives 12. Intermediate 7 was treated with substituted
piperazines under reductive amination conditions to obtain
the 5-piperazinyl methyl indole derivatives 5. Intermediate 5
was further treated with various benzoyl chlorides to obtain
compound 13. Similarly, 5 was treated with various benzyl
chlorides to obtain compound 14 (Scheme 3).
The in vitro 5-HT6R binding assay of all final compounds
was carried out on human recombinant receptor expressed
in HEK293 cells: The radioligand used was [3H] LSD (60-
80 Ci/mmol). The final ligand concentration was 1.5 nM,
and the nonspecific determinant was methiothepin mesy-
late (0.1 μM). The reference compound was methiot-
hepin mesylate, and the positive control was methiothepin
mesylate.
sr. no.
R
R1
X
R2
2-Br
5-HT6 Ki (nM)
6a
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
H
H
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
CO
2.56
5.52
6b
6c
Et
2,3-di-Cl
3-CF3
4-iPr
4-Me
4-F
Et
5.72
6d
6e
Et
5.81
Et
11.0
Among the compounds synthesized (Table 1), compound
6a, which is a 2-bromo benzenesulfonyl indole derivative,
was found to have potent affinity with the Ki of 2.56 nM in the
binding assay. SAR data indicate that the electron-withdraw-
ing groups like halo at the ortho or para position (6a,f,o, 11a,
and 12c) and electron-donating groups like alkyl groups (6d)
at the para position on sulfonyl aromatic ring were found to
be the most preferred substitutions in terms of in vitro
affinity. The halo substitution at the C3 position of the indole
ring was well-tolerated and proved to have greater affinity as
can be seen from the Ki values of compounds 12a and 12c as
compared to those of 6l and 6j, respectively. Replacement of
terminal alkyl substitution R on piperazine with H maintains
the binding affinity toward 5-HT6R, indicating that second-
ary amine seems to be well-tolerated at this position as can
be seen from the Ki values of compounds 6a, 12c, and 12d as
compared to compounds 6q, 11a, and 11b, respectively. The
sulfonyl linker at N1 of indole seems to be very critical for
activity. The replacement of linker with carbonyl (13) or
methylene group (14) gave compounds that have a low
binding affinity toward 5-HT6R.
6f
Et
3.21
6g
Et
2,4-di-F
4-Cl
12.4
6h
6i
Et
28.20
3.83
Me
Me
Me
Me
Me
Me
Me
Me
H
H
6j
4-F
14.6
6k
6l
4-iPr
2-Cl, 5-CF3
2-Br
17.9
11.3
6m
6n
6o
6p
6q
6r
8.30
2,3-di-Cl
4-Cl
18.00
3.02
3-CF3
2-Br
3.15
7.77
H
H
2.52
6s
H
4-iPr
4-F
14.9
11a
11b
12a
12b
12c
12d
13
14
H
2.58
H
2,4-di-F
2-Cl,5-CF3
4-Cl
5.57
Me
Me
Me
Me
Me
Et
4.16
9.33
4-F
2.97
2,4-di-F
H
3.36
Some of the selected potent compounds were evaluated
for their cytochrome P450 inhibitory potential and meta-
bolic stability (Tables 2 and 3, respectively). Low to moderate
levels of inhibition were seen at several of the major human
P450 enzymes with the highest level of inhibition seen
against CYP3A4,26 which was 32.89% inhibition at a 10 μM
>1000
>1000
CH2
H
a Displacement of [3H]-LSD binding to cloned human 5-HT6 recep-
tors stably expressed in HEK293 cells. Ki values were determined in
triplicate.
Table 2. Human Cytochrome P450 Inhibitory Potential of Selected Compoundsa
% inhibition
CYP1A2 (h)
CYP2A6 (h)
CYP2C19 (h)
CYP2C9*1 (h)
3 μM 10 μM
CYP2D6 (h)
CYP3A4 (h)
sr. no.
3 μM
10 μM
3 μM
10 μM
3 μM
10 μM
3 μM
10 μM
3 μM
10 μM
6a
3.64
14.52
13.65
14.44
14.5
17.9
-0.39
-1.26
-7.74
-2.24
-3.62
14.1
10.81
21.89
10.17
4.81
22.76
23.85
6.75
43.59
51.11
4.7
7.47
7.12
15.95
46.27
19.55
18.23
27.75
9.13
48.33
10.45
10.29
11.97
1.46
76.23
35.68
45.98
31.21
17.71
15.23
-3.67
30.52
18.62
8.24
32.89
68.07
34.24
5.47
6d
6f
18.16
8.34
-14.26
-8.69
-12.62
6.42
6i
17.34
14.57
26.92
9.91
31.19
72.92
21.49
11b
12c
6.37
31.85
10.11
26.35
2.6
44.97
39.03
3.4
19.8
6.42
a The cytochrome P450 inhibitory potential was determined using isoform-selective assays and heterologously expressed human CYP1A2, CYP2A6,
CYP2C9*1, CYP2C19, CYP2D6 and CYP3A4. These values are means of duplicate determinations.
r
2010 American Chemical Society
342
DOI: 10.1021/ml100101u ACS Med. Chem. Lett. 2010, 1, 340–344
|

pubs.acs.org/acsmedchemlett
concentration for the lead compound 6a. These results
showed that the compounds from this series would likely
have a lower potential for drug-drug interactions. Com-
pounds 6a,f,o,p and 12c were, however, extensively meta-
bolized in rat and human liver microsomes (Ta bl e 3).
Two of the compounds, 6a and 12c, were examined
further for selectivity against serotonergic and Muscarinic
receptors (Table 4). Both compounds have shown excellent
selectivity over the 5-HT7, 5-HT4, and M1 receptors.
The lead compound 6a, which has shown excellent
binding affinity and selectivity, was selected for pharma-
cokinetic profiling. The pharmacokinetic profile of com-
pound 6a was assessed in male Wistar rats (Table 5 ). The
dose of 10 mg/kg was rapidly absorbed in rats with an oral
half-life of 6.04 ( 2.54 h and had low oral bioavailability.
The observed oral Cmax value was 13 ( 4.0 ng/mL. The
clearance (128367 ( 48173 mL/h/kg) was found to be very
high. Extensive rat metabolism coupled with high clear-
ance could be the reason of low bioavailability (4.2 ( 0.7)
of the lead compound. In a steady-state brain penetration
study in male Wistar rat, the Cb/Cp for 6a was found to be
19.3 ( 5.9.
(Figure 3) in NORTand significantly reversed scopolamine-
induced special memory deficit (Figure 4) in Morris water
maze test, indicating cognitive improvement potential of
compound 6a.
In conclusion, our SAR exploration of N1-aryl sulfonyl
5-methyl piperazinyl indole leads to the finding that moving
the N-methyl piperazinyl moiety from C3 to C5 of indole
maintains the in vitro affinity of these novel compounds.
Two of these potent compounds (i.e., 6a and 12c) have
excellent selectivity over other tested receptors. The lead
compound 6a is active in NORT and Morris water maze,
indicating the cognitive potential of the compound.
Compound 6a was further profiled in animal models of
cognition like novel object recognition test (NORT) and
Morris water maze.27,28 Oral administration of compound
6a has shown improvement in the performance of rats
Table 3. Percent Surrogate Metabolism for Compoundsa
Figure 3. Novel object recognition test in adult rat. *p < 0.05 vs
vehicle (paired t test), n = 9-12/group.
surrogate % metabolism
compound
human
Wistar rat
6a
6f
83
57
59
69
87
100
100
98
6o
6p
12c
98
100
a Microsomal metabolic stability in Wistar rat and human at 0.5 h;
concentration, 2.5 μM.
Table 4. Selectivity Data of Compounds 6a and 12c
IC50 (nM)
compound
5-HT4
5-HT7
M1
Figure 4. Morris water maze. Data represent means ( SEMs of
latency to target; **p < 0.01 (one-way ANOVA, Dunnett's posthoc
analysis), n = 10.
6a
>10000
>10000
>10000
>10000
1425 (kb)
12c
>10000
Table 5. Pharmacokinetic Profile of Compound 6a in Male Wistar Ratsa
compound 6a
route
n
dose (mg/kg)
Cmax (ng/mL)
AUCt (ng h/mL)
t
1/2 (h)
Vz (mL/kg)
Cl (mL/h/kg)
F (%)
oral
iv
3
3
10
10
13 ( 4.0
716 ( 69
59 ( 17
6.04 ( 2.54
2.10 ( 0.18
1035145 ( 240694
21801 ( 3646
128367 ( 48173
7186 ( 764
4.2 ( 0.7
1382 ( 156
a Fasted male Wistar rats. Vehicle used: water for injection for both oral and intravenous routes. Dosing volumes: 10 mL/kg for oral and 2 mL/kg for iv.
r
2010 American Chemical Society
343
DOI: 10.1021/ml100101u ACS Med. Chem. Lett. 2010, 1, 340–344
|

pubs.acs.org/acsmedchemlett
SUPPORTING INFORMATION AVAILABLE Representative
experimental procedures, NMR, MS, and HPLC data for all new test
compounds (6a-s, 11a,b, 12a-d, 13, and 14). This material is
available free of charge via the Internet at http://pubs.acs.org.
antagonist, reverses subchronic PCP-induced cognitive im-
pairment in a rat novel object recognition test. 2nd Biennial
Schizophrenia International Research Conference (SIRS),
Florence, Italy April 10-14th, 2010.
(13) Dukat, M.; Mosier, P. D.; Kolanos, R.; Roth, B. L.; Glennon,
R. A. Binding of serotonin and N1-benzenesulfonyltrypta-
mine-related analogs at human 5-HT6 serotonin receptors:
Receptor modeling studies. J. Med. Chem. 2008, 51, 603–611.
(14) Sikazwe, D.; Bondarev, M. L.; Dukat, M.; Rangisetty, B. J.;
Roth, B. L.; Glennon, R. A. Binding of sulfonyl-containing
arylalkylamines at human 5-HT6 serotonin receptors. J. Med.
Chem. 2006, 49, 5217–5225.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Tel: þ91-40-23556038/23541142. Fax: þ91-40-23541152.
E-mail: ramakrishna_nirogi@yahoo.co.in.
(15) Heal, D. J.; Smith, S. L.; Fisas, A.; Codony, X.; Buschmann, H.
Reduced sensitivity to diet-induced obesity in mice carrying a
mutant 5-HT6 receptor. Pharmacol. Ther. 2008, 117, 207–231.
(16) Epix Pharmaceuticals, Inc. October 29, 2007 press release;
http://www.epixpharma.com.
Funding Sources: The support received from the Discovery
Analytical Department and Venkateswarlu Jasti, CEO, Suven Life
Sciences Ltd., Hyderabad, is gratefully acknowledged.
(17) Nirogi, R.; Kandikere, V.; Mudigonda, K.; Bhyrapuneni, G.;
Jasti, V. Safety, tolerability and pharmacokinetics of SUVN-
ABBREVIATIONS 5-HT, 5-hydroxy tryptamine; 5-HT6R,
5-hydroxy tryptamine 6 receptor; NORT, novel object recog-
nition test; SAR, structure-activity relationship.
502 A 5-HT receptor antagonist, first in human phase-1
;
6
Single Ascending Dose (SAD) study. Alzheimer's Dementia
2009, 5 (4 Suppl.), P250.
(18) Glenon, R. A. Higher-end serotonin receptors: 5-HT5, 5-HT6,
and 5-HT7. J. Med. Chem. 2003, 46, 2795–2812.
REFERENCES
(1)
Woolley, M. L.; Marsden, C. A.; Fone, K. C. F. 5-HT6 receptors.
Curr. Drug Targets CNS Neurol. Disord. 2004, 3, 59–79.
Mitchell, E. S.; Neumaier, J. F. 5-HT6 receptors: A novel target
for cognitive enhancement. Pharmacol. Ther. 2005, 108,
320–333.
(19) Cole, D. C.; Lennox, W. J.; Lombardi, S.; Ellingboe, J. W.;
Bernotas, R. C.; Tawa, G. J.; Mazandarani, H.; Smith, D. L.;
Zhang, G.; Coupet, J.; Schechter, L. E. Discovery of 5-arylsul-
fonamido-3-(pyrrolidin-2-ylmethyl)-1H-indole derivatives as
potent, selective 5-HT6 receptor agonists and antagonists.
J. Med. Chem. 2005, 48, 353–356.
(20) Cole, D. C.; Ellingboe, J. W.; Lennox, W. J.; Mazandarani, H.;
Smith, D. L.; Stock, J. R.; Zhang, G.; Zhou, P.; Schechter, L. E.
N1-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole
derivatives are potent and selective 5-HT6 receptor antago-
nists. Biol. Med. Chem. Lett. 2005, 15, 379–383.
(21) Tsai, Y.; Dukat, M.; Slassi, A.; MacLean, N.; Demchyshyn, L.;
Savage, J. E.; Roth, B. L.; Hufesein, S.; Lee, M.; Glennon, R. A.
N1-(benzenesulfonyl) tryptamines as novel 5-HT6 antago-
nists. Biol. Med. Chem. Lett. 2000, 10, 2295–2299.
(22) Russell, M. G. N.; Baker, R. J.; Barden, L.; Beer, M. S.; Bristow,
L.; Broughton, H. B.; Knowles, M.; McAllister, G.; Patel, S.;
Castro, J. L. N1-arylsulfonylindole derivatives as serotonin
5-HT6 receptor ligands. J. Med. Chem. 2001, 44, 3881–3895.
(23) Shirsath, V. S.; Deshpande, A. D.; Dwarampudi, A. R.; Bhatta,
V.; Bhosale, S. B.; Kota, S.; Kandikere, V. N.; Kambhampati, R.;
Nirogi, R. Novel Substituted Piperazines: New Chemical Class
of Selective 5-HT6 Receptor Antagonist; ACS, Atlanta, GA,
2006; MEDI-142.
(24) Clark, R. D.; Repke, D. H. Heterocycles 1984, 22, 195-222.
(25) Batcho, A. D.; Leimgruber, W. Org. Synth. 1984, 63, 214-224.
(26) Lewis, D. F. V. Cytochromes P450: Structure, Function and
Mechanism; Taylor and Francis Publishing: London, 1996.
(27) Ennaceur, A.; Aggleton, J. P. The effects of neurotoxic lesions
of the perirhinal cortex combined to fornix transection on
object recognition memory in the rat. Behav. Brain. Res. 1997,
88, 181–193.
(28) Jayarajan, P.; Vishwakarma, S. L.; Pendharkar, V. V.; Sharma,
D. C.; Shirsath, V. S.; Nirogi, R. Effect of selective 5-HT6
receptor antagonists in rodent models of learning. Society
for neuroscience 35th annual meeting, Washington, DC, Nov
12-16, 2005.
(2)
(3)
(4)
Fone, K. C. F. An update on the role of the 5-HT6 receptor
in cognitive function. Neuropharmacology 2008, 55, 1015–
1022.
Sleight, A. J.; Boess, F. G.; Bos, M.; Levet-Trafit, B.; Riemer, C.;
Bourson, A. Characterization of Ro 04-6790 and Ro 63-0563:
Potent and selective antagonists at human 5-HT6 receptors.
Br. J. Pharmacol. 1998, 124, 556–562.
(5)
(6)
Boess, F. G.; Riemer, C.; Bos, M.; Bentley, J.; Bourson, A.;
Sleight, A. J. The 5-HT6 receptor-selective radioligand [3H]
Ro63-0563 labels 5-HT receptor-binding sites in rat and
porcine striatum. Mol. Pharmacol. 1998, 54, 577–583.
Bromidge, S. M.; Brown, A. M.; Clarke, S. E.; Dodgson, K.;
Gager, T.; Grassam, H. L.; Jeffrey, P. M.; Joiner, G. F.; King, F. D.;
Middlemeiss, D. N.; Moss, S. F.; Newman, H.; Riley, G.;
Routledge, C.; Wyman, P. 5-Chloro-N-(4-methoxy-3- pipera-
zin-1-ylphenyl)-3-methyl-2-benzothiophenesulfonamide (SB-
271046): A potent, selective, and orally bioavailable 5-HT6
receptor antagonist. J. Med. Chem . 1999, 42, 202–205.
Chuang, A. T. T.; Foley, A.; Pughm, P. L. 5-HT6R antagonist SB-
742457 as a novel cognitive enhancing agent for Alzheimer's
disease. Alzheimer's Dementia 2006, 3, S631-S632 (abstract).
Bruton, G.; Orlek, B. S.; Stemp, G. PCT Int. Appl. WO
2008113818, 2008; Chem. Abstr. 149, 394689.
(7)
(8)
(9)
Robichaud, A. J. Identification of SAM-531 (WAY-262531), a
selective 5-HT6 antagonist for the treatment of cognitive
dysfunction associated with schizophrenia and Alzheimer's
disease. ACS 239th National Meeting and Exposition, San
Francisco, CA, MEDI 34, March 21-25th, 2010.
(10) Geldenhuys, W. J.; Van der Schyf, C. J. The serotonin 5-HT6
receptor: A viable drug target for treating cognitive deficits in
Alzheimer's disease. Expert Rev. Neurother. 2009, 9, 1073–1085.
(11) Kelvin, G. L.; Albert, J. R. 5-HT6 antagonists as potential
treatment for cognitive dysfunction. Drug Dev Res. 2009,
70, 145–168.
(12) Arnt, J.; Bang-Aandersen, B.; Cohen, M. P.; De Lapp, N. W.;
Glethien, B. Lu AE58054, a potent and selective 5-HT6
r
2010 American Chemical Society
344
DOI: 10.1021/ml100101u ACS Med. Chem. Lett. 2010, 1, 340–344
|