Rigidized 1-aryl sulfonyl tryptamines: Synthesis and pharmacological evaluation as 5-HT6 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2011.05.106

A series of N₁-arylsulfonyl-3-(pyrrolidin-3-yl)-1H-indole and N₁-arylsulfonyl-3-(4-chloro-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole derivatives (tryptamine derivatives with rigidized side chain) have been prepared and tested for their binding affinity to 5-HT₆ receptor. Several compounds displayed potent binding affinity for the 5-HT₆ receptor when tested in in vitro binding assay. The primary SAR indicates that rigidification of dimethylamino alkyl chain at C₃ of indole carbon maintains the binding affinity to 5-HT₆R. The lead compound N ₁-benzenesulfonyl-3-(4-chloro-1-methyl-2,5-dihydro-1H-pyrrol-3-yl) -1H-indole, 10a (K_b = 0.1 nM) has shown excellent in vitro affinity and was active in animal models of cognition like NORT and water maze.

Full text of DOI:10.1016/j.bmcl.2011.05.106

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4577–4580
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Rigidized 1-aryl sulfonyl tryptamines: Synthesis and pharmacological
evaluation as 5-HT6 receptor ligands
Ramakrishna Nirogi a, , Adireddy Dwarampudi a,b, Ramasastry Kambhampati a, Venugopalarao Bhatta a,
⇑
Laxman Kota a, Anil Shinde a, Rajesh Badange a, Pradeep Jayarajan a, Gopinadh Bhyrapuneni a, P. K. Dubey b
a Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India
b Department of Chemistry, Jawaharlal Nehru Technological University 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:
A series of N1-arylsulfonyl-3-(pyrrolidin-3-yl)-1H-indole and N1-arylsulfonyl-3-(4-chloro-2,5-dihydro-
1H-pyrrol-3-yl)-1H-indole derivatives (tryptamine derivatives with rigidized side chain) have been pre-
pared and tested for their binding affinity to 5-HT6 receptor. Several compounds displayed potent binding
affinity for the 5-HT6 receptor when tested in in vitro binding assay. The primary SAR indicates that rigid-
ification of dimethylamino alkyl chain at C3 of indole carbon maintains the binding affinity to 5-HT6R. The
lead compound N1-benzenesulfonyl-3-(4-chloro-1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole, 10a
(Kb = 0.1 nM) has shown excellent in vitro affinity and was active in animal models of cognition like NORT
and water maze.
Received 27 April 2011
Revised 25 May 2011
Accepted 27 May 2011
Available online 6 June 2011
Keywords:
5-HT6R antagonist
SAR
Ó 2011 Elsevier Ltd. All rights reserved.
NORT
Water maze
The 5-hydroxytryptamine6 receptor (5-HT6R) which belongs to
the family of 5-HT receptor (5-HT1–5-HT7) is mainly useful in the
modulation of various disorders associated with learning, mem-
ory1–3 and feeding behavior.4,5 5-HT6R is a stimulatory G-protein
coupled receptor which activates adenyl cyclase. Northern blot
analysis has shown that the 5-HT6R is expressed mainly in the brain,
particularly high levels of 5-HT6R mRNA present in the olfactory
tubercle, cortex, nucleus accumbens, striatum, hippocampus, cere-
bellum and hypothalamus.6,7 A through literature search reveals
that several antipsychotic and antidepressant drugs have significant
affinity for 5-HT6R.8,9 The specific localization of 5-HT6 receptors in
CNS and high affinity of antipsychotic and antidepressant drugs
have promoted interest in this receptor as a promising target for
schizophrenia, anxiety, impairment of learning, memory and obes-
ity.10–17 Since then, many 5-HT6R ligands have been reported and
some of the clinically advancing molecules include SB-742457,18
SUVN-502,19 Lu AE58054,20 SAM-76021 and SYN-114.22 Indole nu-
cleus is one of the most explored chemical class of 5-HT6R ligands,
which include the N1-arylsulfonyl tryptamines, for example, MS-
24523 and 2-aryl tryptamines, for example, PMDT.24 Mooradian et
al. has published the 5-HT6R binding activity for some carbazole
derivatives, which are conformationally restricted tryptamines.25
N1-Arylsulfonyl tryptamines, viz: MS-245, where the dimethyl-
amino ethyl side chain at C-3 of indole is relatively flexible, is a
known ligand at 5-HT6R with high affinity (Ki = 2.1 nM). Our study
was aimed at investigating the effect of rigidification of tryptamine
side-chain, bearing terminal nitrogen. The side chain has been rig-
idized by incorporation into a five membered pyrrolidine ring.
Based on the literature precedence, the minimum pharmacophore
components of 5-HT6R ligands are one protonizable nitrogen and
two hydrophobic motifs.26 The molecules of template 5 and 10
have all these features and hence we envisioned that these mole-
cules would also have high affinity towards 5-HT6 receptors. The
results of these efforts are the subject matter of this paper.
Cl
R1
N
R1
N
N
O
R
R
Modify
Rigidification
R2
N
O S
O
R2
N
O S
O
N
O S
O
10
5
MS-245
⇑
Corresponding author. Tel.: +91 40 23556038/23541142; fax: +91 40 23541152.
E-mail address: ramakrishna_nirogi@yahoo.co.in (R. Nirogi).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.106

4578
R. Nirogi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4577–4580
Table 2
O
N
O
5-HT6R binding affinities of N1-arylsulfonyl-3-(4-chloro-2,5-dihydro-1H-pyrrol-3-yl)-
1
O
R
O
O
1H-indole derivativesa
b
a
1
R
N R
Cl
N
R1
O
N
H
N
O
R
2
1
3
R2
1
R
N
R
1
O S
R
R
N
c
d
O
R
2
N
O S
O
N
Compound
R
R1
R2
Kb (nM)
H
4
5a-j
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
H
H
H
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
CH3
CH3
CH3
C2H5
CH3
CH3
CH3
CH3
C2H5
H
4-Br
4-F
4-OCH3
2-Br
4-Br
4-F
3-Cl
H
2-Br
4-Br
4-F
3-Cl
4-OCH3
4-CH(CH3)2
2, 4, 5-Cl
H
2-Br
4-Br
4-F
3-Cl
4-OCH3
H
0.10 0.03
0.35 0.05
0.60 0.20
10.00 1.00
1.10 0.30
3.90 0.50
5.80 0.50
12.52 0.70
0.10 0.02
0.30 0.10
1.78 0.30
0.63 0.20
0.84 0.16
1.65 0.25
0.25 0.15
18.45 0.95
0.70 0.20
6.15 0.95
4.75 0.25
8.70 0.80
2.40 0.02
14.5 1.20
1.00 0.30
0.40 0.10
4.45 0.50
6.16 0.70
0.45 0.15
0.70 0.25
7.27 1.05
0.10 0.04
0.25 0.10
6.15 1.10
Scheme 1. Reagents and conditions: (a) CH3COOK, AcOH, R1NH2ÁHCl, 110 °C, 4 h,
30–35%; (b) Mg, MeI, substituted indoles, THF/toluene, 70 °C, 3–4 h, 65–70%; (c)
LAH, THF, reflux, 2–3 h, 70–75%; (d) substituted arylsulfonyl chlorides, NaH, DMF,
RT, 3–4 h, 65–75%.
O
N
O
Cl
R1
O
O
O
O
Cl
Cl
Cl
Cl
b
a
N R1
R
N
H
O
6
7
8
Cl
R1
N
Cl
R1
R
N
10s
10t
d
c
R
N
O S
O
R2
10u
10v
10w
10x
10y
10z
10aa
10ab
10ac
10ad
10ae
10af
N
H
9
10a-af
2-Br
4-Br
4-F
2-Br
H
F
H
2-Br
3-Cl
Scheme 2. Reagents and conditions: (a) CH3COOK, AcOH, R1NH2ÁHCl, 110 °C, 4 h,
70–75%; (b) Mg, MeI, substituted indoles, THF/toluene, 70 °C, 3–4 h, 70–75%; (c)
LAH, THF, reflux, 2–3 h, 25–30%; (d) substituted arylsulfonyl chlorides, NaH, DMF,
RT, 3-4 hrs, 65-75%.
OCH(CH3)2
OCH(CH3)2
F
F
F
Table 1
The compounds were tested in vitro using nonradioactive cell-based assay for
determination of Kb values at 5-HT6R.
5-HT6R binding affinities of N1-arylsulfonyl-3-(pyrrolidin-3-yl)-1H-indole deriva-
tivesa
The reported Kb values are mean of three experiments.
R1
N
a
All compounds were characterized and purity was assessed using 1H NMR, MS
R
and HPLC.
N
O S
O
R2
by reaction of appropriately substituted maleic anhydride with al-
kyl amines in presence of acetic acid and potassium acetate.27 The
latter were reacted with appropriately substituted indoles28–30 un-
der Grignard conditions to obtain 3-substituted pyrrolidine diones
(intermediates 3 and 8).31,32 These dione intermediates were re-
duced with lithium aluminum hydride to obtain intermediates 4
and 9, which were further reacted with substituted aryl sulfonyl
chlorides to obtain the targeted compounds (5a–j and 10a–af).
In vitro binding affinities were determined for all the synthe-
sized compounds using functional reporter gene based assay.33,34
This assay uses a stable CHO cell line expressing recombinant hu-
man 5-HT6R and pCRE-Luc reporter system which refers a nonra-
dioactive based approach to determine binding of a compound to
GPCRs. By using this specific assay, the level of intracellular cyclic
AMP which is modulated by activation or inhibition of the receptor
is measured.
Compound
R
R1
–
R2
Kb (nM)
MS-245
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
–
H
H
H
–
H
4-F
5.8 0.25
1.52 0.15
1.00 0.30
0.13 0.07
0.10 0.03
0.89 0.11
0.13 0.02
0.10 0.04
1.30 0.20
0.10 0.02
4.15 0.50
CH3
CH3
CH3
C2H5
CH3
CH3
CH3
C2H5
CH3
CH3
2-Br
2-Br
H
2-Br
4-CH(CH3)2
2-Br
2-Br
2-Br
H
OCH3
OCH3
OCH3
OCH3
OC2H5
OCH(CH3)2
The compounds were tested in vitro using nonradioactive cell-based assay for
determination of Kb values at 5-HT6R.
The reported Kb values are mean of three experiments.
a
All compounds were characterized and purity was assessed using 1H NMR, MS
and HPLC.
As part of SAR studies, several analogues of N1-arylsulfonyl-3-
pyrrolidinyl indole (5a–j) were synthesized and their Kb values
are given in Table 1. All the compounds were tested as racemates.
In this series all the reported compounds were found to be high
affinity ligands with Kb values <5 nM. This high affinity shows that
the rigidification of dimethylamino alkyl chain at C-3 carbon of
MS-245 is tolerated in terms of 5-HT6 receptor binding. Substitu-
N1-Arylsulfonyl-3-(pyrrolidin-3-yl)-1H-indole (5a–j) and N1-
arylsulfonyl-3-(4-chloro-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole
(10a–af) compounds were prepared by a sequence of reactions
shown in Schemes 1 and 2. Intermediates 2 and 7 were prepared

R. Nirogi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4577–4580
4579
Table 3
Pharmacokinetic profile of compound 10aa
Compound 10a
Route
n
Dose (mg/kg)
Cmax (ng/mL)
AUCt (ng h/mL)
t1/2 (h)
Vz (mL/kg)
Cl (mL/min/kg)
F (%)
12
Oral
i.v.
3
3
10
10
105 27
2694 656
268 61
2319 404
3.75 1.32
5.48 0.81
19,6287
34,868
584.8
72.53
4
a
Fasted male Wistar rats, vehicle used: water for injection for both oral and i.v. routes. Dosing volumes: 10 mL/kg for oral and 2 mL/kg for i.v.
in sub-nanomolar concentration range. Substitution on the phenyl
portion of indole C-5 with electron donating groups like methoxy
(10i, 10j), ethoxy (10w, 10x) and isopropoxy (10ab), electron with-
drawing group like fluoro (10ad, 10ae) have resulted in compounds
with excellent affinities at 5-HT6R.
In general, unsubstituted phenyl sulfonyl analogs have shown
excellent affinity compared to substituted phenyl sulfonyl analogs.
Small liphophilic substituents like fluoro, chloro, bromo or meth-
oxy substitution on the phenyl sulfonyl ring were well tolerated
and it seems there is a slight preference for ortho substitution.
Replacing the methyl substituent on the amine with ethyl has re-
tained the 5-HT6R binding affinities (10i and 10q).
Selected compounds that showed excellent potency in in vitro
binding assay were further profiled for their selectivity for a panel
of receptors including serotonin subtypes, transporters, adrenergic
and muscarnic receptors. The compounds (10a, 10b, 10c, 10i, 10j
and 10n) have excellent selectivity over a range of closely related
receptors like 5-HT2A, 5-HT2C, 5-HT4, 5-HT7, histamine H1, dopa-
mine D2, adrenergic a1b, muscarinic acetylcholine receptor M1
and the transporters like SERT, DAT and NET. All the tested com-
Figure 1. Novel object recognition test data for compound 10a in rats. ⁄⁄p <0.01
versus vehicle (paired t test), n = 8–12/group, p.o., dosing; 60 min prior to test.
Vehicle – PEG 400 50% v/v; 1 mL/kg, p.o.
pounds produced <50% inhibition at a concentration of 0.5
(data not shown).
lM
tion at C-5 carbon of indole ring, with electron donating groups like
methoxy (5f), ethoxy (5i) and isopropoxy (5j) groups was well tol-
erated. The compounds with halo and alkyl substitutions on phenyl
sulfonyl ring as well as unsubstituted phenyl sulfonyl group were
tolerated.
The in vitro metabolic stability of compounds 10a and 10i in rat
and human liver microsomes was carried out for 30 min. Compound
10i has extensively metabolized (96% and 97%) compared to com-
pound 10a (70% and 43%) in rat and human, respectively. The IC50
values for compound 10a was found to be 21.1
lM for CYP 2D6
Encouraged by the above in vitro results, we explored the modi-
fications around pyrrolidine ring. Several analogues of N1-arylsulfo-
nyl-3-(4-chloro-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole (10a–af)
were synthesized and their Kb values are given in Table 2. Introduc-
tion of double bond (unsaturation) and chloro substitution in the
pyrrolidine ring did have a favorable effect on the binding affinities.
Most of the compounds have shown high 5-HT6R binding affinities,
and 14.7 M for CYP 3A4. Brain penetration is an important property
l
for agents targeting CNS disorders. Brain and plasma levels were cal-
culated in male Wister rats after 6 h i.v. continuous infusion of com-
pound 10a at 1 mg/kg/h dose. This compound has shown adequate
brain to plasma ratio of 1.79. The pharmacokinetic profile of 10a
was assessed in Wister rats (Table 3). Following i.v. administration
of 10 mg/kg, the mean half-life was 5.48 0.81 h and the average
60
55
50
45
40
35
30
25
20
15
10
5
PEG 400 50% (1 mL/kg, p.o.) + WFI (1 mL/kg, i.p.)
PEG 400 50% (1 mL/kg, p.o.) + Scopolamine (0.6-0.8 mg/kg, i.p.)
Donepezil (0.3 mg/kg, i.p.) + Scopolamine (0.6-0.8 mg/kg, i.p.)
Compound 10a (10 mg/kg, p.o.) + Scopolamine (0.6-0.8 mg/kg, i.p.)
**
*
*
**
0
Day 1
Day 2
Day 3
Day 4
Day 5
Data
Figure 2. Latency to target in Morris water maze test data for compound 10a in rats. Data represents Mean SEM of latency to target, ⁄p <0.05, ⁄⁄p <0.01 (One Way ANOVA,
Dunnett’s post hoc analysis).

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