Design, synthesis and pharmacological evaluation of 4-(piperazin-1-yl methyl)-N1-arylsulfonyl indole derivatives as 5-HT6 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2012.10.057

4-(Piperazin-1-yl methyl)-N₁-arylsulfonyl indole derivatives were designed and synthesized as 5-HT₆ receptor (5-HT₆R) ligands. The lead compound 6a, from this series shows potent in vitro binding affinity, good PK profile,

Full text of DOI:10.1016/j.bmcl.2012.10.057

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7431–7435
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and pharmacological evaluation of 4-(piperazin-1-yl
methyl)-N1-arylsulfonyl indole derivatives as 5-HT6 receptor ligands
Ramakrishna V. S. Nirogi a, , Rajeshkumar Badange a,b, Ramasastri Kambhampati a, Anil Chindhe a,
⇑
Amol D. Deshpande a, Vinaykumar Tiriveedhi a, Vishwottam Kandikere a, Nageswararao Muddana a,
Renny Abraham a, Mukkanti Khagga b
a Discovery Research, Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India
b Institute of Science and Technology, JNTU Hyderabad, Kukatpally, Hyderabad 500 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 July 2012
Revised 18 September 2012
Accepted 11 October 2012
Available online 17 October 2012
4-(Piperazin-1-yl methyl)-N1-arylsulfonyl indole derivatives were designed and synthesized as 5-HT6
receptor (5-HT6R) ligands. The lead compound 6a, from this series shows potent in vitro binding affinity,
good PK profile, no CYP liabilities and activity in animal models of cognition.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
5-HT6R ligands
Cognitive impairment
SAR
Cross selectivity
PK profile
ORT
Cognitive impairment is one of the defining symptoms of many
severe neurological disorders such as Alzheimer’s disease, demen-
tia, Parkinson’s disease, Schizophrenia, etc. and in recent years
5-HT6R attracted lot of focus and became a promising target for
the treatment of these neurological disorders.1–3 One of the main
reasons for this trend is due to their exclusive expression in brain
regions known to be associated with learning and memory.4 5-HT6
receptor was first identified by molecular cloning in rats followed
by man and then in mouse.5–7 They are positively coupled to aden-
ylyl cyclase, and the receptor antagonism leads to increased pro-
duction of cAMP.8 Studies have found that known 5-HT6R
antagonists significantly increased glutamate and acetylcholine
levels in frontal cortex without elevating the levels of dopamine,
noradrenalin or serotonin.9 This selective elevation of neurochem-
icals known to be involved in memory and cognition, strongly sug-
gests a role of 5-HT6R ligands in cognition.9 These facts, like
exclusive CNS location and high affinity of several antipsychotics
and antidepressants10,11 towards this receptor, suggests 5-HT6R li-
gands may become forefront treatment methods for neurological
disorders and gained considerable interest from research commu-
nities12–19 across the world.
Till date a number of potent compounds with strong affinity to
5-HT6R were reported which are in various stages of clinical devel-
opment. Antagonists like SB-74245720 and Lu AE5805421 (Fig. 1)
are in phase 2 clinical trials whereas MS-24522 and SB-69992923
were among the early discovered potent, 5-HT6R antagonists.
Majority of these compounds have a basic amine moiety and two
hydrophobic aryl functionalities, which are thought to be basic
pharmacophoric requirements for 5-HT6R binding.24
Several diverse scaffolds were reported in the literature where
modifications were done on the side chain of tryptamines.25 We fo-
cused our attention on alkyl piperazines and other cyclic amines as
they were not much studied and evaluated on indole nucleus and
initiated our research in this direction and in recent past we have
published a few reports in this area.26 In addition to these, we have
also identified 5-piperazinyl methyl-N1-aryl sulfonyl indole deriv-
ative, that is, Compounds I (Fig. 2) which were potent and selective
5-HT6R antagonists.27 As a part of our ongoing research to identify
5-HT6R ligands as potential treatment options for CNS diseases, we
continued with our strategy of making changes in the position of
CH2 piperazinyl moiety on indole and moved CH2 piperazinyl moi-
ety in Compounds I from C5 of indole to C4 of indole. Thus, we ob-
tained a new series, that is, Compounds II (Fig. 2) which contain all
the pharmacophoric requirements for 5-HT6R binding and hence
we expect these compounds to be potent 5-HT6R ligands. In this
⇑
Corresponding author. Tel.: +91 40 23556038/23541142; fax: +91 40 23541152.
E-mail address: nvsrk@suven.com (R.V.S. Nirogi).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.057

7432
R. V. S. Nirogi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7431–7435
The N-desmethyl compounds 14 were synthesized by adopting
F
F
O
F
the following strategy (Scheme 3). Indole-4-carboxaldehyde 11
was reacted with N-boc-4-piperazine using NaBH3CN in ethylene
dichloride (EDC) to get intermediate 12 which was further treated
with various substituted benzenesulfonyl chlorides in presence of
NaH to obtain intermediates 13. These intermediates 13 were
deprotected in MeOHꢀHCl to obtain final compounds 14 as corre-
sponding HCl salts.
O
O
F
S
HN
N
N
N
F
N
H
H
The in vitro 5-HT6R binding assay of all final compounds was
carried out on human recombinant receptor expressed in HEK293
cells: Radioligand used was [3H]-LSD (60–80 Ci/mmol). Final ligand
concentration was 1.5 nM, Non-specific determinant was methio-
Lu AE58054
H
N
SB-742457
H3C
CH3
N
thepin mesylate—[0.1 lM]; reference compound was methiothepin
mesylate, positive control was methiothepin mesylate.
N
O
Cl
H3C
All the synthesized compounds were tested for their binding
affinity towards 5-HT6 R (Table 1). As part of SAR studies, we ini-
tially synthesized 4-(4-methylpiperazin-1-yl methyl)-1H-indole
with unsubstituted benzenesulfonyl group, that is, compound 6c
and it was found to be active with a potent binding affinity of
Ki = 3.24 nM in binding assay. Encouraged with the result, we used
various alkyl, alkoxy, halo and other substituted benzenesulfonyl
chlorides for N1-substitution of indole nucleus to assess their effect
on binding affinities. Among these, compound 6a with 2-
bromobenzenesulfonyl group was found to be the most potent
compound with a Ki = 1.43 nM. The compound 6b, Ki = 4.82 nM
with naphthalenesulfonyl ring was equipotent compared to unsub-
stituted compound 6c. Replacement of 2-bromobenzenesulfonyl
group in compound 6a with 4-bromo and 4-methoxy substitution,
gave compounds 6i, Ki = 23.41 nM and 6j, Ki = 29.15 nM, respec-
tively with a reduction in binding affinity by 16- to 20-fold. The
other halogen substituted compounds viz. 6f, Ki = 9.89 nM and
6h, Ki = 13.17 nM were found to maintain the potent binding affin-
ities towards 5HT6R. We then focused our attention to analyse the
effect of alkyl substitution on the benzenesulfonyl ring and made
compounds 6d, Ki = 7.92 nM and 6g, Ki = 11.13 nM with 4-meth-
ylbenzenesulfonyl and 4-isopropylbenzenesulfonyl rings, respec-
tively which were 2- to 3-fold more potent compared to
compound 6i. Compound 6e, Ki = 8.58 with disubstituted benzene-
sulfonyl group also maintained potent binding affinity. From the
above SAR data, we observed that both electron donating groups
like methyl (6d), isopropyl (6g), electron withdrawing groups like
fluoro (6f), chloro (6h) have resulted in compounds with excellent
affinities towards 5-HT6R. This trend in Ki values confirms that
both electron withdrawing and electron donating groups on ben-
zenesulfonyl ring are well tolerated. Even bulky 1-naphthylsulfo-
nyl group is also well tolerated at N1 position of indole (6b).
We then explored the effect of halo substitution on indole nu-
cleus by introducing Cl, Br at C-3 position of indole. This change re-
sulted in the compounds with less potent binding affinities. For
example, compound 8b, Ki = 53.6 nM having Cl substitution on C-
3 position of indole and compound 10a, Ki = 30.2 nM having Br sub-
stitution on C-3 position of indole were less potent by 16-fold and
10-fold, respectively when compared to parent compound 6c,
Ki = 3.24 nM. This trend continued for other compounds in the ser-
ies as well. Replacement of N-methyl substitution on piperazine
with H (which could be the possible metabolite) maintains the
binding affinity towards 5-HT6R, indicating that secondary amine
seems to be well tolerated at this position (Table 1, compare 14a,
14b and 14c vs. 6a, 6c and 6d, respectively). From the SAR data,
we came to the conclusion that C-3 deshalo indole compounds
are more preferable over C-3 halo substituted indole compounds.
At this point of SAR, we thought that it could be interesting to
compare binding affinities of some of the above select compounds
with Compounds-I.27 Compounds 6a, 6c, 6f, 6g and 14a of
Compounds-II were more potent than their respective counter-
parts belonging to Compounds-I. This proves that the concept of
N
S
O
N
S
O
O
O
Cl
MS-245
SB-699929
Figure 1. Some of the potent 5-HT6R antagonists reported in literature.
report we brought forward the details of synthesis, SAR and phar-
macological data of Compounds II.
A generalised synthetic approach for the proposed compounds
was shown in Schemes 1–3. 3-Nitro-2-methyl benzoic acid 1
(Scheme 1) was treated with thionylchloride followed by N-meth-
ylpiperazine to obtain the amidic intermediate 2. This amide com-
pound was reacted with N,N-dimethylformamide dimethylacetal
(DMFDMA) and pyrrolidine28 to obtain styrene intermediate 3.
This styrene intermediate 3 underwent reductive cyclization and
gave indole intermediate 4 upon treatment with Raney Ni and
hydrazine hydrate. This intermediate 4 having amide functionality
was reduced with lithium aluminium hydride (LAH) to 4-(4-meth-
ylpiperazin-1-yl methyl)-1H-indole 5. N1-Sulfonylation of interme-
diate 5 with substituted benzenesulfonyl chlorides in presence of
NaH gave the final compounds 6.
The following strategy was adopted to prepare final compounds
8 and 10 (Scheme 2). 4-(4-Methylpiperazin-1-yl methyl)-1H-
indole 5 was treated with N-chlorosuccinimide (NCS) and N-bro-
mosuccinimide (NBS) to obtain 3-chloro-4-(4-methylpiperazin-1-yl
methyl)-1H-indole intermediate 7 and 3-bromo-4-(4-methylpi-
perazin-1-yl methyl)-1H-indole intermediate 9, respectively. N1-
Sulfonylation of intermediate 7 was carried out with substituted
benzenesulfonyl chlorides in presence of NaH to obtain title com-
pounds 8. A similar strategy was followed to synthesize final com-
pounds 10 from intermediate 9.
R
N
N
R1
R1
N
N
N
N
R
SO2
SO2
R2
R2
Compounds II
Compounds I
Figure 2. Rationale for 4-(piperazin-1-yl methyl)-N1-arylsulfonyl indoles (Com-
pounds II).

R. V. S. Nirogi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7431–7435
7433
H3C
N
CH3
N
N
N
O
O
N
COOH
CH3
a
b
c
CH3
NO2
65 % over 3 steps
NO2
NO2
1
2
3
H3C
N
H3C
H3C
N
N
N
O
N
N
d
e
60 - 75%
70 %
N
N
H
N
H
SO2
4
R2
5
6
Scheme 1. Synthesis of 4-(4-methylpiperazin-1-yl methyl)-N1-arylsulfonyl indoles 6. Reagents and conditions: (a) Thionylchloride, EDC, DMF (catalytic), reflux for 3 h then
N-methylpiperazine, 10 °C to room temperature, 0.5 h. (b) DMFDMA, DMF, pyrrolidine, 100–110 °C, 6 h. (c) Hydrazine hydrate, Raney Nickel, methanol, 70 °C, 3 h. (d) LAH,
THF, 68 °C, 5 h. (e) THF, NaH, substituted benzenesulfonyl chlorides, room temperature, 3 h.
H3C
N
N
Cl
H3C
N
N
N
Cl
c
SO2
55 - 70 %
N
a
H
H3C
N
R2
7
N
55 %
8
H3C
N
N
H
N
H3C
N
Br
b
N
5
Br
58 %
c
N
SO2
52 - 65 %
N
H
9
R2
10
Scheme 2. Synthesis of 3-halo-4-(4-methylpiperazin-1-yl methyl)-N1-arylsulfonyl indoles 8 and 10. Reagents and conditions: (a) NCS, 1,4-dioxane, room temperature, 4 h.
(b) NBS, 1,4-dioxane, room temperature, 4 h. (c) THF, NaH, substituted benzenesulfonyl chlorides, room temperature, 3 h.
moving CH2 piperazinyl moiety in Compounds I from C5 of indole
to C4 of indole has a favourable effect in terms of binding affinities
to 5HT6R.
The high selectivity of this series towards off-targets and low inhi-
bition towards human ether-a-go-go-related gene (hERG) are
important findings which suggests limited disturbance due to fore-
seen add-on therapies, low possibility of QT prolongation and max-
imize safety.
Compounds 6a and 6c were further evaluated for their CYP lia-
bilities, microsomal metabolic stability (Table 4) and pharmacoki-
netic profile (Table 5). Both the compounds 6a and 6c were
extensively metabolized in rat liver microsomes whereas in human
liver microsomes, compound 6a was extensively metabolized
(90%) and compound 6c was moderately metabolized (47%). The
effect of compounds 6a and 6c on cytochrome P450 enzymes in
human liver microsomes were determined. The IC50 values for
The most potent compounds 6a and 6c from the series were se-
lected for testing their functional activity at 5-HT6R using non-
radioactive CHO based cell assay. These tested compounds showed
antagonistic activity by inhibiting the 5-HT stimulated cAMP accu-
mulation as can be seen from the IC50 and Imax values (Table 2).
A number of compounds that displayed satisfactory potency to-
wards 5-HT6R in binding assay were profiled for their selectivity
against a panel of closely related receptors and transporters at
1
l
M concentration. In general, these compounds have shown
excellent selectivity over all the receptors examined (Table 3).

7434
R. V. S. Nirogi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7431–7435
CH3
O
O
CH3 O
O
H3C
H3C
H3C
H3C
HN
2HCl
N
N
N
N
N
CHO
N
a
b
c
N
H
70 %
60 - 75 %
N
N
H
85 - 90 %
SO2
SO2
11
12
R2
R2
13
14
Scheme 3. Synthesis of 4-(piperazin-1-yl methyl)-N1-arylsulfonyl indoles 14. Reagents and conditions: (a) N-Boc-4-piperazine, CH3COOH, NaBH3CN, EDC, room temperature,
8 h. (b) THF, NaH, substituted benzenesulfonyl chlorides, room temperature, 3 h. (c) MeOHꢀHCl, diethyl ether, room temperature, 4 h.
Table 1
Table 2
5-HT6 receptor binding data of Compounds IIa
Functional activity dataa
R
N
Compound
Kb (nM)
IC50 (nM)
Imax (%)
6a
6c
0.59 0.36
1.02 1.47
135.1 19.79
233.5 46.66
100 0.14
99 0.07
N
R1
a
Kb values were determined using non-radioactive cell based assay. IC50 and Kb
values are the mean of two experiments.
N
2'
SO2
3'
compounds 6a and 6c at CYP 3A4 were found to be 35.97% and
6'
30.50%, respectively, whereas the IC50 values at CYP 2D6 enzymes
were found to be less than 20 lM. These results show that the
4'
5'
R2
compounds from this series have lower potential for drug–drug
interaction.
Compound
R
R1 R2
5-HT6R Ki
(nM)
The pharmacokinetic profile of compounds 6a and 6c were as-
sessed in male wistar rats (Table 5). Compound 6a at an oral dose
of 10 mg/kg was rapidly absorbed in rats with a good oral half-life
of 3.17 0.49 h with an oral bioavailability of 29 5%. The ob-
served oral Cmax was 60 44 ng/mL and occurred at 1.83 h. The
compound displayed an oral exposure of 217 92 ng h/mL. It had
a clearance of 220 92 mL/min/kg with a volume of distribution
of 32.6 10.7 L/kg for iv dose. Extensive rat metabolism coupled
with high clearance could be the possible reason for moderate oral
bioavailability showed by compound 6a. Compound 6c displayed
poor overall pharmacokinetic profile and was not profiled further.
In steady state brain penetration study in Male Wistar Rat, Cb/Cp for
6a was found to be 20.33.
Compound 6a was further profiled in animal models of cogni-
tion like Object Recognition Task30 (ORT). Oral administration of
compound 6a reversed the time delay induced memory deficit
and statistically significant effect was observed at a dose of
10 mg/kg (Fig. 3) indicating cognitive improvement potential of
the compound 6a.
6a
6b
CH3
CH3
H
H
20-Br
1.43 0.021
4.82 0.045
R2 together with benzene ring is 1-
naphthyl
H
6c
6d
6e
6f
6g
6h
6i
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
3.24 0.041
7.92 0.055
8.58 0.079
9.89 0.12
11.13 0.26
13.17 0.18
23.41 0.21
29.15 0.27
27.19 0.23
53.62 0.84
99.70 1.54
165 2.68
40-CH3
20-Br, 40-O CH3
40-F
40-iPr
30-Cl
40-Br
6j
40-O CH3
8a
8b
8c
8d
CH3 Cl 30-Cl
CH3 Cl
CH3 Cl 40-iPr
H
CH3 Cl R2 together with benzene ring is 1-
naphthyl
8e
8f
10a
10b
10c
CH3 Cl 40-CH3
CH3 Cl 20-Br
CH3 Br
CH3 Br 30-Cl
222 4.06
90.71 1.48
30.28 0.3
75.30 1.39
H
CH3 Br R2 together with benzene ring is 1- 97.61 1.81
naphthyl
10d
10e
14a
14b
14c
CH3 Br 40-F
CH3 Br 40-iPr
H
H
H
122 2.51
278 6.12
2.82 0.025
7.84 0.15
10.72 0.21
In conclusion, we have disclosed a new series of Compounds II,
that is, 4-(4-methylpiperazin-1-yl methyl)-N1-arylsulfonyl indole
derivatives, obtained by moving CH2 piperazinyl moiety in Com-
pounds I from C5 of indole to C4 of indole. The new series of Com-
pounds II, thus disclosed herein, have potent in vitro binding
affinities towards 5-HT6R. The lead compound 6a from this series
has shown excellent binding affinity with good pharmacokinetic
H
H
H
20-Br
H
40-CH3
Displacement of [3H]-LSD binding to cloned human 5-HT6 receptors stably
expressed in HEK293 cells. Ki values were determined in duplicate and the average
values are reported here. The binding assays were carried out at Novascreen Bio-
sciences Corporation, USA as per their standard protocol.
a
Table 3
Compound cross selectivity dataa
Compound
a1B
5-HT2A
5-HT3
D2
D3
DAT
3.66
3.92
20.39
3.53
NET
SERT
H1
9.48
10.12
9.33
2.38
9.82
hERG
6a
6c
8a
10a
14a
2.26
0.99
0.78
2.17
1.13
23.98
10.94
17.67
19.31
18.73
18.82
6.73
19.92
8.93
11.08
7.26
12.93
5.01
27.8
10.83
10.16
13.5
6.78
6.28
4.62
2.85
1.51
5.27
8.47
15.75
21.07
20.24
22.97
24.52
22.61
28.47
35.72
8.31
17.99
12.8
5.23
a
Values given in% inhibition at 1 lM concentration and are measured by competitive displacement of corresponding radioligand. Values are mean of two experiments.

R. V. S. Nirogi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7431–7435
7435
Table 4
Human CYP45029 inhibitory data and microsomal metabolic stabilitya
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
10.057.
Compound
IC50
CYP 3A4
(l
M)
% Metabolism in liver microsomes
CYP 2D6
Human
Rat
6a
6c
35.97
30.50
19.50
16.80
90
47
100
100
a
The cytochrome P450 inhibitory potential was determined using isoform-
References and notes
selective assays and heterologously expressed human CYP 2D6 and CYP 3A4. These
values are the mean of duplicate determinations. Microsomal metabolic stability in
Wistar Rat and Human at 0.5 h, Con. 2.5 lM.
1. Roth, B. L.; Hanizavareh, S. M.; Blum, A. E. Psychopharmacology 2004, 174, 17.
2. Rosse, G.; Schaffhauser, H. Curr. Top. Med. Chem. 2010, 10, 207.
3. Wilson, C.; Terry, A. V., Jr. Drugs Future 2009, 34, 969.
4. Gerard, C.; Martres, M. P.; Lefevre, K.; Miquel, M. C.; Verge, D.; Lanfumey, L.;
Doucet, E.; Hamon, M.; Mestikawy, S. E. Brain Res. 1997, 746, 207.
5. Monsma, F. J.; Shen, Y.; Ward, R. P.; Hamblin, M. W.; Sibley, D. R. Mol.
Pharmacol. 1993, 43, 320.
6. Ruat, M.; Traiffort, E.; Arrang, J. M.; Tardivellacombe, J.; Diaz, J.; Leurs, R.;
Schwartz, J. C. Biochem. Biophys. Res. Commun. 1993, 193, 268.
7. Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.; Lachowicz, J. E.;
Meltzer, H. Y.; Sibley, D. R.; Roth, B. L.; Hamblin, M. W. J. Neurochem. 1996, 66,
47.
Table 5
Pharmacokinetic profile of compounds 6a and 6c in male Wister ratsa
Compound
6a
6c
iv
t1/2 (h)
Vz (L/kg)
CL (mL/min/kg)
1.76 0.76
32.6 10.7
220 40
1.53 0.35
19.4 0.74
152 43
8. Sleight, A. J.; Boess, F. G.; Bos, M.; Levet-Trafit, B.; Bourson, A. Exp. Opin. Ther.
Patents 1998, 8, 1217.
po
9. (a) Dawson, L. A.; Nguyen, H. Q.; Li, P. Neuropsychopharmacology 2001, 25, 662;
(b) Dawson, L. A.; Nguyen, H. Q.; Li, P. Br. J. Pharmacol. 2000, 130, 23.
10. Arnt, J.; Olsen, C. K. Int. Rev. Neurobiol. 2011, 96, 141.
11. Roth, B. L.; Craigo, S. C.; Choudhary, M. S.; Uluer, A.; Monsma, F. J.; Shen, Y.;
Meltzer, H. Y.; Sibley, D. R. J. Pharmacol. Exp. Ther. 1994, 268, 1403.
12. Liu, K. G.; Robichaud, A. J. Drug Dev. Res. 2009, 70, 145.
13. Holenz, J.; Pauwels, P. J.; Diaz, J. L.; Merce, R.; Codony, X.; Buschmann, H. Drug
Discovery Today 2006, 11, 283.
Cmax (ng/mL)
Tmax (h)
AUCt (ng h/mL)
F (%)
60 44
1.83 1.89
217 92
7.6 3.3
1.08 0.88
23 11
29
5
2
1
a
Fasted male wistar rats, Vehicle used: water for injection for both oral and
intravenous routes. Dosing volumes: 10 mL/kg po and 2 mL/kg for iv.
14. Codony, X.; Vela, J. M.; Ramirez, M. J. Curr. Opin. Pharmacol. 2011, 11, 94.
15. Emsley, R. Expert Opin. Investig. Drugs 2009, 18, 1103.
16. Fone, K. C. F. Neuropharmacology 2008, 55, 1015.
Open Column - Familiar Object
Filled Column - Novel Object
16
17. Mitchell, E. S.; Neumaier, J. F. Pharmacol. Ther. 2005, 108, 320.
18. Glennon, R. A.; Siripurapu, U.; Roth, B. L.; Kolanos, R.; Bondarev, M. L.; Sikazwe,
D.; Lee, M.; Dukat, M. Curr. Top. Med. Chem. 2010, 10, 579.
19. Davies, S.; Silvestre, J. S.; Guitart, X. Drugs Future 2005, 30, 479.
20. Maher-Edwards, G.; Dixon, R.; Hunter, J.; Gold, M.; Hopton, G.; Jacobs, G.;
Hunter, J.; Williams, P. Int. J. Geriatr. Psychiatry 2011, 26, 536.
21. Arnt, J.; Bang-Andersen, B.; Grayson, B.; Bymaster, F. P.; Cohen, M. P.; DeLapp,
N. W.; Giethlen, B.; Kreilgaard, M.; McKinzie, D. L.; Neill, J. C.; Nelson, D. L.;
Nielsen, S. M.; Poulsen, M. N.; Schaus, J. M.; Witten, L. M. Int. J.
Neuropsychopharmacol. 2010, 13, 1021.
14
**
12
10
8
6
22. Tsai, Y.; Dukat, M.; Slassi, A.; MacLean, N.; Demchyshyn, L.; Savage, J. E.; Roth,
B. L.; Hufesein, S.; Lee, M.; Glennon, R. A. Bioorg. Med. Chem. Lett. 2000, 10,
2295.
4
23. Ahmed, M.; Briggs, M. A.; Bromidge, S. M.; Buck, T.; Campbell, L.; Deeks, N. J.;
Garner, A.; Gordon, L.; Hamprecht, D. W.; Holland, V.; Johnson, C. N.; Medhurst,
A. D.; Mitchell, D. J.; Moss, S. F.; Powles, J.; Seal, J. T.; Stean, T. O.; Stemp, G.;
Thompson, M.; Trail, B.; Upton, N.; Winbornc, K.; Witty, D. R. Bioorg. Med. Chem.
Lett. 2005, 15, 4867.
2
0
24. Liu, K. G.; Robichaud, A. J. Int. Rev. Neurobiol. 2010, 94, 1.
25. Glennon, R. A. J. Med. Chem. 2003, 46, 2795.
Vehicle
Compound 6a 10 mg/kg
26. (a) Nirogi, R.; Dwarampudi, A.; Kambhampati, R.; Bhatta, V.; Kota, L.; Shinde,
A.; Badange, R.; Jayarajan, P.; Bhyrapuneni, G.; Dubey, P. K. Bioorg. Med. Chem.
Lett. 2011, 21, 4577; (b) Nirogi, R.; Deshpande, A.; Kambhampati, R.; Badange,
R.; Kota, L.; Daulatabad, A.; Shinde, A.; Ahmad, I.; Kandikere, V.; Jayarajan, P.;
Dubey, P. K. Bioorg. Med. Chem. Lett. 2011, 21, 346; (c) Nirogi, R.; Daulatabad, A.;
Parandhama, G.; Mohammad, S.; Sastri, K. R.; Shinde, A.; Dubey, P. K. Bioorg.
Med. Chem. Lett. 2010, 20, 4440.
27. Nirogi, R.; Kothmirkar, P.; Kambhampati, R.; Konda, J.; Arepalli, S.; Pamuleti, N.;
Deshpande, A.; Bandyala, T.; Shinde, A.; Dubey, P. K. ACS Med. Chem. Lett. 2010,
1, 340.
Figure 3. Object Recognition Task of compound 6a in male wistar rat. Data
represents mean SEM of exploration time (Paired ‘t’ test), ⁄P < 0.05). Vehicle—PEG
400 50% v/v; 1 mL/kg, po n = 6–9 /group, po dosing vehicle/drug: 60 min prior to
test (po).
profile, acceptable selectivity at other closely related receptors and
is active in animal models of cognition. The compound 6a, based
on its overall profile, was selected for further development.
28. (a) Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195; (b) Batcho, A. D.;
Leimgruber, W. Org. Synth. 1985, 63, 214.
29. Lewis, D. F. V. Cytochromes P450: Structure, Function and Mechanism; Taylor and
Francis Publishing: London, 1996.
Acknowledgements
The support received from discovery analytical department and
Mr. Venkateswarlu Jasti, CEO, Suven Life Sciences Ltd., Hyderabad
is gratefully acknowledged.
30. Ennaceur, A.; Aggleton, J. P. Behav. Brain Res. 1997, 88, 181.