Sulfonamides with the N-alkyl-N′-dialkylguanidine moiety as 5-HT7 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2009.06.038

A series of arylsulfonamides containing guanidine incorporated in the structure of secondary amines (piperidine, piperazine) was synthesized on SynPhase Lanterns and evaluated for 5-HT_1A, 5-HT_2A, and 5-HT₇ receptors. The r

Full text of DOI:10.1016/j.bmcl.2009.06.038

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4827–4831
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Sulfonamides with the N-alkyl-N0-dialkylguanidine moiety as 5-HT7
receptor ligands
b
b
a
c
c
Paweł Zajdel a, , Gilles Subra , Pascal Verdie , Ewa Gabzdyl , Andrzej J. Bojarski , Beata Duszynska ,
*
´
Jean Martinez b, Maciej Pawłowski a
a Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
b Department of Amino Acids, Peptides and Proteins, Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, University Montpellier I and II, 15 Charles Flahault,
34-093 Montpellier, France
c Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Sme˛tna Street, 31-343 Kraków, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of arylsulfonamides containing guanidine incorporated in the structure of secondary amines
(piperidine, piperazine) was synthesized on SynPhase Lanterns and evaluated for 5-HT1A, 5-HT2A, and
5-HT7 receptors. The results demonstrated that N-alkyl-N0-dialkylguanidines displayed good 5-HT7/5-
HT1A selectivity and may be regarded as promising structural core for development of 5-HT7 ligands.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 6 April 2009
Revised 6 June 2009
Accepted 10 June 2009
Available online 13 June 2009
Keywords:
Serotonin
Sulfonamides
Guanidines
Arylpiperazines
Solid-phase synthesis
5-HT1A
5-HT7 receptor ligands
The actions of 5-hydroxytryptamine (5-HT), one of the major
modulatory neurotransmitters in the central nervous system
(CNS), are mediated by a number of receptors grouped in seven
families. Scientific interest has focused on the most recently iden-
tified 5-HT subtype—the 5-HT7 receptor. On the basis of CNS local-
ization (thalamus, hypothalamus, hippocampus, amygdala) and
pre-clinical pharmacological investigation, it has been hypothe-
sized that 5-HT7 receptors may be involved in affective disorders
and mood regulation connected with sleep and circadian rhythms.1
It is also worth noting that several antipsychotic drugs exhibit a
high affinity for 5-HT7 receptors.2
The knowledge of the involvement of 5-HT7 receptors in the
pathomechanism of psychiatric disorders has been improved by
the development of selective agonists and antagonists, as well as
due to the findings of several in vivo investigations.3 Those works
have proven that model 5-HT7 antagonists (e.g., SB-269970) are
efficacious in animal models of depression and anxiety.4,5 Based,
among others, on this fact, it has recently been hypothesized that
5-HT7 antagonists seem promising in the process of elaboration
of novel antidepressants with improved efficacy and devoid of a
long onset of action.6
5-HT7 receptor antagonists, followed by many SAR studies, have
been described in a few reviews.7,8 Among this class of molecules, a
variety of sulfonamide derivatives with different aliphatic and aro-
matic secondary amine fragments occupy a prominent position
(Fig. 1). Our interest focused on guanidine moiety since it may be
regarded as one of crucial components of medicinally interesting
molecules acting on CNS.9–11 In particular it was found to be an
essential part in the structure of several 5-HT receptor ligands
affecting affinity and/or selectivity.12–15 Recently, a number of
derivatives containing an amidino-urea fragment have been de-
scribed as 5-HT7 ligands (Fig. 2).16
Taking account of the above-mentioned findings, we designed a
small library of compounds containing both the sulfonamide moi-
ety and a guanidine motif incorporated in the secondary amine
(e.g., piperidine or piperazine). Structural modifications also com-
prised diversification of the length (C2–C4) of an alkylene spacer
between sulfonamide and a molecule’s basic center, and finally
the kind of an arylsulfonyl fragment to determine the effect of ste-
ric properties. To efficiently obtain the designed compounds, we
took advantage of a solid-phase methodology and developed a ro-
bust, parallel synthetic route to sulfonamide derivatives of N-alkyl-
* Corresponding author. Tel.: +48 12 620 54 50; fax +48 12 657 02 62.
E-mail address: mfzajdel@cyf-kr.edu.pl (P. Zajdel).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.06.038

4828
P. Zajdel et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4827–4831
HO
O
S
O
N
N
N
S
O
O
I
SB-269970
N
H
H
N
N
O
N
S
S
N
O
O
O
O
O
N
II
III
Figure 1.
N
H
H
N
H
N
H
N
N
O
N
NH
NH
O
O
NH
O
IV
V
Figure 2.
N0-dialkylguanidines (12, Scheme 1). The affinity of the selected li-
brary members was preliminarily tested for 5-HT1A, 5-HT2A, and 5-
HT7 receptors.
ethylene spacer showed low purity (16–52%). For other library
members: the overall yields, calculated on the basis of the initial
loading of the Lanterns, were between 24% and 48%, the purity val-
ues ranging from 73% to 99% (Table 1). Finally, eight library mem-
bers were purified using a reverse-phase preparative LC/MS ESI
automated system (Waters Micromass). The yielded compounds
were submitted to biological assays. Selected library representa-
tives were tested in competition binding experiments for native
5-HT1A (rat hippocampus), 5-HT2A (rat cortex), and cloned human
5-HT7 (stably expressed in HEK-293 cells) receptors, according to
the previously published procedures.20,21
Interestingly enough, the investigated compounds showed good
affinity for 5-HT7 receptors, which ranged from 140 to 339 nM, and
very low activity at 5-HT1A receptors (Ki = 1.09–17.59 lM). Consid-
ering 5-HT2A receptor affinity, the reported compounds displayed
good-to-low affinities ranging from 148 to 1251 nM (Table 2). In
the series of investigated compounds neither the linker length
nor the kind of arylsulfonyl fragment significantly influenced affin-
ity for 5-HT receptors.
As part of ongoing efforts towards identification of selective 5-
HT7 receptor ligands several research groups focused on arylsul-
fonamides connected by an alkylene spacer with diverse secondary
amine fragments (e.g., alkyl/aryl-piperidines or piperazines). It was
demonstrated that the affinity of sulfonamide derivatives for 5-HT7
receptors was often accompanied with high affinity for 5-HT1A sub-
types.25,26 From the comparison between biological activity of the
new derivatives and their close analogs without guanidine moiety
(12{2,3,4} and 12{1,2,4} vs II and III, Fig. 6) it comes out that the
introduction of delocalized positive charge in the ionic center of
molecule generally attenuated affinity for the tested 5-HT recep-
tors. Interestingly, the relatively small decrease in activity was ob-
served for 5-HT2A and 5-HT7 receptors, and at the same time all the
The general synthetic approach to the guanidine derivatives is
presented in Scheme 1. The key starting Fmoc-protected diam-
inoalkanes (Fig. 3), prepared from corresponding diamines, were
loaded to BAL Lanterns in an optimized one-pot reductive ami-
nation, involving NaBH3CN in a 10% solution of AcOH in a mix-
ture of DMF/MeOH (50:50, v/v), the reaction taking place at a
room temperature for 24 h. The subsequent coupling of second-
ary amines (3) with sulfonyl chlorides (diversity reagents 4;
Fig. 4) in the presence of TEA in DCM yielded resin-bound sul-
fonamides 5. Typically, the preparation of guanidines involves a
reaction of amines with electrophilic amidine derivatives, pro-
tected by Boc groups.17,18 Since such
a
protection was not
orthogonal with our BAL linkage strategy, we treated deprotec-
ted primary amines (6) with Fmoc-isothiocyanate and obtained
thiourea derivative 7. Next, after Fmoc removal, the intermediate
product (8) was submitted to double treatment with a MeI solu-
tion in DMF at a room temperature for 1 h to yield S-methyl
derivative 9. N-Alkyl-N0-alkylguanidines (11) were achieved via
replacement of the methylthio group of 9 with representatives
of diverse secondary amines (Fig. 5), the reaction taking place
in an anhydrous DMSO at 80 °C for 24 h. The final products
(12) were obtained upon treatment with a mixture of TFA/
DCM 95:5 (v/v) for 2.5 h.
Based on initially optimized conditions, a library containing 36
derivatives was synthesized in a parallel manner by a split-and-
pool approach on Syn-Phase Lanterns.19 The Lanterns were
equipped with colored cogs and spindles. The isolated products
were found to be of moderate-to-high purity. Surprisingly, under
optimized conditions, the obtained representatives containing an

P. Zajdel et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4827–4831
4829
O
i
MeO
O
O
=
O
N
2{1-3}
H
H
H
N
N
H
Fmoc
n
H
OMe
1
3
ii, 4{1-3}
iii
R
R
H
NH2
N
N
N
S
S
Fmoc
n
n
O
O
O
O
6{1-3;1-3}
5{1-3;1-3}
iv
v
R
H
H
R
H
N
N
N
N
NH2
N
O
Fmoc
S
S
n
n
O
O
O
S
S
7{1-3;1-3}
8{1-3;1-3}
vi
vii
R
H
N
R
H
N
10{1-4}
N
N
NH
N
S
S
n
n
O
O
O
O
NH
S
9{1-3;1-3}
11{1-3;1-3; 1-4}
viii
R
H
n = 0, 1, 2
4-methylpiperidine,
H
N
N
N
S
n
4-phenylpiperidine,
=
tetrahydroisoquinoline,
2-methoxyphenylpiperazine
O
O
N
NH
12{1-3;1-3; 1-4}
Scheme 1. Solid phase synthesis routes for sulfonamide 12: (i) Diversity reagent 2{1–3}, NaBH3CN, DMF/MeOH/AcOH 45:45:10 (v/v/v), rt, 24 h; (ii) Diversity reagents 4{1–3},
DMF, TEA, rt, 2 ꢀ 2.5 h; (iii, v) 20% piperidine/DMF; (iv) FmocNSC, DCM, rt, 2 ꢀ 1 h; (vi) MeI, DMF, 2 ꢀ 1 h; (vii) Diversity reagent 10{1–4}, DMSO, 80 °C, 24 h; (viii) TFA, 2.5 h.
H
N
H
H
O
NH2
O
N
O
N
NH2
NH2
O
O
O
2{1}
2{2}
2{3}
Figure 3. Protected aliphatic diamines, 2{1–3}.
compounds (except 12{1,1,1} and 12{3,3,3}) were practically inac-
tive for 5-HT1A receptors. In this way selectivity of the new com-
pounds significantly increased over 5-HT1A receptors (from 6 to
80-fold). This finding seems to be of special value since classic
long-chain arylpiperazines, especially those containing ortho-
methoxyphenyl fragment, were classified as highly active 5-HT1A
receptor ligands26,27 or dual 5-HT1A and 5-HT7 receptor li-
O
O
O
O
O
O
S
S
S
Cl
Cl
Cl
4{1}
4{2}
4{3}
Figure 4. Diverse sulfonyl chlorides, 4{1–3}.

4830
P. Zajdel et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4827–4831
N
HN
HN
HN
HN
O
10{1}
10{2}
10{3}
10{4}
Figure 5. Diverse secondary amines, 10{1–4}.
Table 1
Table 2
Analytical data for library
Affinity data for 5-HT1A, 5-HT2A, and 5-HT7 receptors for library representatives
Compda
Purityb (%)
MW calcd
[M+H]+ found
Compd
Ki [nM]a
12{1,1,1}
12{1,1,2}
12{1,1,3}
12{1,1,4}
12{1,2,1}
12{1,2,2}
12{1,2,3}
12{1,2,4}
12{1,3,1}
12{1,3,2}
12{1,3,3}
12{1,3,4}
12{2,1,1}
12{2,1,2}
12{2,1,3}
12{2,1,4}
12{2,2,1}
12{2,2,2}
12{2,2,3}
12{2,2,4}
12{2,3,1}
12{2,3,2}
12{2,3,3}
12{2,3,4}
12{3,1,1}
12{3,1,2}
12{3,1,3}
12{3,1,4}
12{3,2,1}
12{3,2,2}
12{3,2,3}
12{3,2,4}
12{3,3,1}
12{3,3,2}
12{3,3,3}
12{3,3,4}
33
17
17
19
11
21
31
18
52
42
35
30
91
100
73
91
88
90
95
93
91
89
96
78
88
96
88
83
87
97
97
87
87
81
87
91
338.18
400.19
372.26
431.2
338.18
400.19
372.16
431.2
374.18
436.19
408.19
467.2
339.22
421.21
373.22
432.3
339.22
401.27
373.22
432.31
375.18
437.25
409.3
468.27
353.27
415.27
387.21
446.24
353.27
415.27
387.21
446.24
389.24
451.25
423.25
482.22
367.27
429.33
401.27
460.3
5-HT1A
5-HT2A
5-HT7
SB-269970b
Ic
>10,000
35
4.6
—
520
>4000
1098
4555
10,420
17,590
9860
12,050
10,200
2080
>10,000
65
85
1.2
8
20
75
6
IId
IIIe
—
IVf
150
400
148
160
1146
1251
940
770
340
195
Vf
49
12{1,1,1}
12{1,1,2}
12{1,1,4}
12{2,1,2}
12{2,3,4}
12{3,1,2}
12{3,2,4}
12{3,3,3}
177
161
339
276
195
150
140
198
352.2
414.21
386.51
445.21
352.19
414.21
386.51
445.21
388.19
450.21
422.18
481.21
366.21
428.22
400.19
459.23
366.2
428.22
400.19
459.23
402.21
464.22
436.57
495.23
a
The estimated Ki values (see Ref. 20) were calculated from three independent
binding experiments with SEM 622%.
b
Data taken from Ref. 22.
Data taken from Ref. 23.
Data taken from Ref. 24.
Data taken from Ref. 25.
c
d
e
f
Data taken form Ref. 16.
366.4
429.27
401.27
460.3
403.32
465.31
437.25
496.28
N
H
H
N
N
N
O
S
O
O
NH
12{2,3,4}
a
Library members encoded as 12{Diversity reagent 2, Diversity reagent 4, Diversity
NH
reagent 10}.
H
N
b
Determined by integration of the peak area at k = 214 nm.
S
N
H
N
O
O
O
N
gands.24,28–30 Introduction of guanidine moiety into the structure
of 5-HT ligands may now be considered as a method for designing
more selective 5-HT7 receptor agents.
12{1,1,4}
Figure 6.
Summing up, the synthesis and preliminary 5-HT7, 5-HT1A, and
5-HT2A receptor activities of the series of guanidines incorporated
in the structure of diverse well-known secondary amines with a
potential application to CNS disorders have been described. We
identified compounds possessing good affinity for 5-HT7 and 5-
HT2A receptor, displaying selectivity over 5-HT1A receptors. Further
studies aimed at improvement of 5-HT7 receptor binding will be
reported in due course.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.06.038.
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The study was partly supported by the Polish Ministry of Sci-
ence and Higher Education (MNiSW), Grant No. 2-P05F-019-30.

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