Benzimidazolone-based serotonin 5-HT1A or 5-HT7R ligands: Synthesis and biological evaluation

Article abstract of DOI:10.1016/j.bmcl.2009.02.008

A new group of serotoninergic 5-HT_1A or 5-HT₇ receptor ligands was identified. These compounds were designed and synthesized on a benzimidazolone scaffold and they enrich the well-known arylpiperazine class of 5-HT ligands. Diverse p

Full text of DOI:10.1016/j.bmcl.2009.02.008

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1600–1603
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Benzimidazolone-based serotonin 5-HT1A or 5-HT7R ligands: Synthesis
and biological evaluation
c
b
a
Eduard Badarau a,b, Franck Suzenet a, , Andrzej J. Bojarski , Adriana-Luminißta Fînaru , Gérald Guillaumet
*
a Institut de Chimie Organique et Analytique, Université d’Orléans, UMR-CNRS 6005, UFR Sciences - BP 6759, rue de Chartres, 45067 Orléans Cedex 2, France
b Centrul de Cercetare ‘Chimie Aplicata˘ ßsi Inginerie de Proces’, Universitatea din Baca˘u Calea Ma˘ra˘ßsesti, nr. 157, 600115 Baca˘u, Romania
c Institute of Pharmacology, Polish Academy of Sciences, Sme˛tna 12, Kraków 31-343, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A new group of serotoninergic 5-HT1A or 5-HT7 receptor ligands was identified. These compounds were
designed and synthesized on a benzimidazolone scaffold and they enrich the well-known arylpiperazine
class of 5-HT ligands. Diverse pharmacomodulations induced a shift in the affinity and selectivity profile
with final identification of new potent hits.
Received 9 December 2008
Revised 4 February 2009
Accepted 4 February 2009
Available online 8 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Benzimidazolone
5-HT7Rs Ligands
Arylpiperazines
Among the seven subtypes of receptors that mediate the seroto-
nin (5-HT) functions,1 the 5-HT7Rs are the latest discovered
(1993).2–4 Their distribution both in the central nervous system
and in the peripheral tissues5,6 is highly associated with their
implications in psychiatric disorders,7,8 depression, anxiety and
mood,9–12 learning and memory,13–15 epilepsy,16 inflammatory
processes,17–19 ileum peristalsis,20,21 just to cite a few recent stud-
ies on 5-HT7R complex system.
Many ligands have been reported to bind with high affinity to 5-
HT7 receptors and their number is continuously increasing.22–24
The advantage of a wide variety of completely different chemical
patterns published to date may rapidly turn into a drawback
making the understanding of a common binding pattern more dif-
ficult, especially when not enough SAR data associated with every
class of ligand is available. Simple pyridines 125 and more complex
structures as triazine 226 or pyrazole 327 may serve as examples
(see Fig. 1).
Arylpiperazines, initially discovered as 5-HT1AR ligands, show
also good affinities for 5-HT7Rs, most probably due to the strong
similarities between the binding sites of these receptors.28,32,41 In
the present Letter, we enrich the class of arylpiperazine 5-HT1A
/
5-HT7R ligands, with the discovery of a new heterocyclic scaffold
able to accommodate in the receptor-binding site, namely the
benzimidazolone skeleton. The applied structural modifications
influenced the 5-HT1A and 5-HT7Rs affinities as well as selectivity
profile of the investigated compounds.
Our starting point was the 5-HT7/5-HT1A ligand 4 previously
published by Rault and co-workers.42 (Ki = 4.3 nM and Ki = 9.9 nM,
respectively). The replacement of the central pyrrole with benzim-
idazolone was investigated in a first approach in order to evaluate
the influence of this new heteroaromatic scaffold on the 5-HT7R/5-
HT1ARs affinity. The initial series, with a two-carbon linker, was
A number of studies defining 5-HT7 pharmacophoric models
have also been published,28–34 and a recent review summarized
them in the context of all the 5-HTRs.35 Also, some 5-HT7R homol-
ogy models using Rho crystal structures as templates were
proposed.29,30,32,36 It is highly probable that recently solved struc-
tures of first GPCRs from the aminergic family37–39 will enhance
the research in 5-HT7R area by supplying better templates for
homology studies (for a review see Nichols et al.40).
* Corresponding author. Tel.: +33 02 38 49 45 80; fax: +33 02 38 41 72 81.
E-mail address: franck.suzenet@univ-orleans.fr (F. Suzenet).
Figure 1. 5-HT7 diversity ligands.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.008

E. Badarau et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1600–1603
1601
Table 1
Binding affinities for compounds 8a–h
Compound
R1
R2
5-HT1A Kia (nM)
5-HT7 Kia (nM)
8a
8b
8c
8d
8e
8f
H
H
H
H
H
Me
Me
Me
OMe
467
636
646
340
168
375
182
22
1230
902
864
2-Me
3-OMe
4-OMe
H
2-Me
3-OMe
4-OMe
566
1867
17,960
2500
296
8g
8h
a
Values are means of three experiments run in triplicate, SEM 6 12%.
cloned human 5-HT7 (stably expressed in HEK-293 cells) receptors,
according to the previously published procedures.46
As shown in Table 1, for unsubstituted phenyl A (R2 = H) the 5-
HT7R affinity increases as the substituents on the phenyl B are
more remote from the benzimidazolone central skeleton (entries
8a–d). The introduction of a methyl substituent on the aromatic
ring A (R2 = Me) has a major negative impact on the 5-HT7 affinity,
while rather improving affinities for 5-HT1ARs (see entries 8e–g). It
is well known that ortho-methoxy substituent on the phenylpiper-
azine moiety enhances the 5-HT1A affinity. Following this assump-
tion, we synthesized the compound 8h to check if this trend is also
confirmed in the case of our benzimidazolone-based ligands. The
best Ki values are observed indeed in the case of R2 = OMe; the
compound 8h shows an affinity of 22 nM on 5-HT1ARs.
Figure 2. Orthogonal views of GASP (SYBYL) superposition between compound 4
(green) and the designed benzimidazolone analog (blue).43
Because the overall affinities of these compounds were higher
for 5-HT1AR, in order to improve the biological activities on the
5-HT7Rs, two structural changes were applied: (a) an increase of
the linker length and (b) removal of the aryl moiety B. The above
modifications were based on structures of some published long
chain arylpiperazine (LCAP) ligands such as 9,47 10,33 and more re-
cently 1148 and 1249 (see Fig. 3) which incorporated 4–5 carbon
atoms in the linker in order to obtain a higher 5HT7 affinity. The
impact of the spacer’s length on the 5-HT1A/5-HT7Rs selectivity
was also the subject of a previously published paper, which con-
cluded that, in the case of arylpiperazine 5-HT7R ligands, a more
flexible compound could adopt more easily the active conforma-
tion within the binding receptor.50
Scheme 1. Reagents and conditions: (i) NaH, Boc2O/DMF/10 h, rt, 89%; (ii) R1–
PhB(OH)2, Cu(OAc)2, TEMPO or PNO, TEA, Air/DCM, m.s. 4 Å/2–4 d, rt, 62–70%; (iii)
TFA/DCM/2 h, rt, 99%; (iv) 1,2-dibromoethane, K2CO3, Bu4NBr or Bu4NI/H2O/10 h,
reflux, 70–90%; (v) arylpiperazine, K2CO3/THF/15–30 min, 160 °C, mw, 54–93%; (vi)
fumaric acid (2 equiv)/MeOH, Et2O/10 min, 35 °C, 99%.
The synthetic strategy was more convergent, that is, the cross-
coupling step followed the introduction of the phenylpiperazine
moiety (Scheme 2).
The synthesis started with the Boc protection of one benzimi-
dazolone nitrogen as previously described. In the next step, the
remaining nitrogen was alkylated with different dibromoalkanes
(3–6 carbon atoms linker). The subsequent substitution of bromine
supported by a good superposition between these two structures
(see Fig. 2).
The developed synthetic route is detailed in Scheme 1.
After protection of one benzimidazolone’s nitrogen with a Boc
group, the second was coupled with various substituted aryls.
The coupling procedure described by Lam et al.44 was applied with
commercially available boronic acids. Acidic deprotection of Boc
group was followed by nitrogen alkylation with 1,2-dibromoeth-
ane in water, using potassium carbonate as base and tetrabutylam-
monium bromide (or iodide) as phase transfer catalyst. The
subsequent substitution of bromine with diverse arylpiperazines
was initially performed under classical heating conditions. Since
long reaction times were required for the total conversion of the
starting material (usually 1–2 days), the reaction was optimized
under microwave irradiation. In general, 15–30 min at 160 °C in
THF were sufficient for the completion of the reaction. An addi-
tional step involved the conversion of final oily compounds into
their corresponding solid salts. Fumaric acid was found appropri-
ate, and 2 equiv were required for quaternisation of two nitrogens
(as proven by 1H NMR spectra).45
All the final compounds were tested in competition binding
experiments for native serotonin 5-HT1A (rat hippocampus), and
Figure 3. Examples of LCAP 5-HT7 ligands.

1602
E. Badarau et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1600–1603
Table 3
Binding affinities for compounds 15a–j
Compds
n
R2
5-HT1A Kia (nM)
5-HT7 Kia (nM)
15a
15b
15c
15d
15e
15f
15g
15h
15i
2
2
3
3
4
4
5
5
6
6
H
392
25
26
3.4
84
6
269
33
48
12
1029
1838
243
40
48
26
6
38
20
78
2-OMe
H
2-OMe
H
2-OMe
H
2-OMe
H
15j
2-OMe
a
See Table 1 for details.
Table 4
Binding affinities for compounds 15k and 15m
Compds
n
R2
5-HT1A Kia (nM)
5-HT7 Kia (nM)
Scheme 2. Reagents and conditions: (i) NaH, Boc2O/DMF/10 h, rt, 89%; (ii) 1,2-
dibromoalcane, K2CO3, Bu4NI/H2O/10 h, reflux, 73–90%; (iii) arylpiperazine, K2CO3/
THF/15–30 min, 160 °C, mw, 74–93%; (iv) R1–PhB(OH)2, Cu(OAc)2, TEMPO or PNO,
TEA, Air/DCM, m.s. 4 Å/3 d, rt, 32–40%; (v) fumaric acid (2 equiv)/MeOH, Et2O/
10 min, 35 °C, 99%.
15k
15m
5
5
3-Cl
4-Cl
66
454
11
7
a
See Table 1 for details.
Table 2
profile. These compounds were synthesized in the same way as
indicated in Scheme 2, using appropriate phenylpiperazines for
the step (iii). The corresponding affinities are given in Table 4.
The 4-Cl substitution on phenylpiperazine moiety enhanced 65-
fold the selectivity profile of compound 15m in the favor of 5-
HT7Rs. On the other hand, in the case of ligand 15k, the 3-Cl sub-
stitution does not improve its binding qualities compared to the
non-substituted compound 15g.
Binding affinities for compounds 17d and 17f
Compds
n
R1
R2
5-HT1A Kia (nM)
5-HT7 Kia (nM)
8h
17d
17f
2
3
4
4-OMe
4-OMe
4-OMe
2-OMe
2-OMe
2-OMe
22
26
36
296
168
267
a
See Table 1 for details.
In conclusion, we identified new benzimidazolone derivatives
able to selectively bind to 5-HT7 receptors over the 5-HT1ARs. We
also demonstrated the influence of the phenyl-piperazine moiety
on the 5-HT7R selectivity and the impact of the aliphatic linker
on the 5-HT1A/5-HT7Rs affinity. Further pharmacological studies
are currently conducted in order to improve the biological proper-
ties of our best hits 15g and 15m, the benzimidazolone skeleton
being easily modulated on the aromatic ring.
with aryl-piperazines was conducted as before. The Boc group was
also removed during this step, which was in accordance with a pre-
vious study on the mild deprotection of amines.51
To evaluate the influence of the linker’s length on N-arylated
benzimidazolone compounds, both 14d and 14f were N-arylated
using p-methoxyphenylboronic acid as a coupling partner produc-
ing 17d and 17f, respectively (Table 2).
The increased linker length does not have an important effect
on 5-HT1A/5-HT7 affinity, since both 17d and 17f showed compara-
ble affinities as compound 8h. Because of the overall lower 5-HT7R
affinities of N-arylated compounds than unsubstituted derivatives
(vide infra) further studies on these structures were abandoned.
As a next step, the influence of the linker’s length of the NH free
benzimidazolones on the 5-HT1A/5-HT7Rs affinity was evaluated.
This structure simplification is beneficial both to 5-HT1A and 5-
HT7 receptor affinity (Table 3). In the case of 5-HT1A receptors,
the previously reported tendency of enhanced affinity of the o-
methoxy derivatives compared to the non-substituted analogs
was also confirmed for our compounds (see couples 15b/15a,
15d/15c, 15f/15e and 15h/15g). For these receptors, the optimum
3 carbons linker induced an affinity of 3.4 nM in the case of ligand
15d.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.02.008.
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