Novel benzofuran derivatives with dual 5-HT1A receptor and serotonin transporter affinity

Article abstract of DOI:10.1016/j.bmcl.2009.12.093

Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT_1A receptor affinities. Their design, synthesis and structure-activity relationships are described.

Full text of DOI:10.1016/j.bmcl.2009.12.093

Bioorganic & Medicinal Chemistry Letters 20 (2010) 824–827
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel benzofuran derivatives with dual 5-HT1A receptor and serotonin
transporter affinity
a
a
b
b
Aranapakam M. Venkatesan a, , O. Dos Santos , John Ellingboe , Deborah A. Evrard , Boyd L. Harrison ,
*
Deborah L. Smith c, Rosemary Scerni c, Geoffrey A. Hornby c, Lee E. Schechter c, Terrence H. Andree c
a Chemical Sciences, Wyeth Research, Pearl River, NY 10965, United States
b Chemical Sciences, Wyeth Research, CN8000, Princeton, NJ 08543-8000, United States
c Neuroscience Discovery Research, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were pre-
pared and evaluated for serotonin transporter and 5-HT1A receptor affinities. Their design, synthesis and
structure–activity relationships are described.
Received 6 November 2009
Revised 21 December 2009
Accepted 24 December 2009
Available online 4 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
SSRI
5HT-1A
Benzofuran
Selective serotonin reuptake inhibitors (SSRIs) have achieved
great success in treating depression and related conditions. SSRIs
act by blocking the neuronal reuptake of serotonin (5-HT), increas-
ing the concentration of synaptic 5-HT and thus, increasing the
activation of post synaptic 5-HT receptor; however, they suffer
from a delayed onset of action.1 This delay in antidepressant activ-
ity is speculated to be the result of acute stimulation of the soma-
todendritic 5-HT1A auto receptors that decrease neuronal firing to
release 5-HT in the forebrain. Only after desensitization of these
autoreceptors do the serotonergic neurons resume normal firing
and eventually lead to an increase in 5-HT levels in the major fore-
brain areas.2–4 It can take two to three weeks before the patient
feels the full antidepressant effect. This delayed onset of action is
a significant problem, especially in the patients with severe
depression. It has been shown by Arborelius et al.5 that acute
administration of SSRIs reduces firing of 5-HT neurons of dorsal
raphe nucleus in the rodent brain and sustained treatment of SSRIs
leads to normalization of the firing activity of the 5-HT neurons.
Furthermore, it has been shown by Invernizzi et al.6 that the recov-
ery of firing activity of the 5-HT neurons is linked to desensitiza-
tion of somatodendritic 5-HT1A autoreceptors. Hence it has been
suggested that simultaneous administration of an SSRIs and a 5-
HT1A antagonist would lead to a rapid onset of antidepressant
effect.7
Pre-clinical evidence has shown that acute SSRI-induced in-
creases in forebrain 5-HT can be significantly augmented by co-
treatment with either pindolol or the more selective 5-HT1A antag-
onist WAY-100635.7,8 It has been shown by Dawson et al.9 that the
co-administration of fluoxetine and WAY-100635 produces an
immediate increase in 5HT levels in rat frontal cortex, as evidenced
by in vivo microdialysis, where this effect was not seen with fluox-
etine treatment alone. This ‘immediate’ onset was strongly sup-
ported in the clinical trials conducted by Artigas et al10 and Blier
et al.1 These researchers have demonstrated that combination of
racemic pindolol, a non-selective 5-HT1A antagonist with the SSRI
paroxetine shortened the onset of antidepressant action to a period
of 3–7 days in contrast to the 2–3 weeks required with the SSRI
alone. Therefore, incorporating both the antagonism of the 5-
HT1A receptor and 5-HT reuptake inhibition of the 5-HT transporter
within a single molecule should provide an immediate increase of
5-HT in the frontal cortex, resulting in a more rapid onset of anti-
depressant action.9,10,1
Previous reports from our laboratories have revealed four novel
series (Fig. 1) capable of modulating both SSRI and 5-HT1A receptor
activitiesbylinking an aryloxyethylamine1 and3 or a benz[1,4]oxa-
zine 2 and 4 with a 3-indoletetrahydropyridine or a 3-indolealkyl-
amine 1 and 2 through a common basic nitrogen.11–13 In all these
series, an aryloxy ethylamine moiety has been utilized to produce
potent 5-HT1A ligands, while the indole tetrahydropyridine or indole
alkyamine portion have served as the 5-HT uptake inhibitor sub-
structure. In order to expand upon the type of structures that can
potentially maintain both desired activities and to probe the
* Corresponding author. Tel.: +1 845 602 4023; fax: +1 845 602 5561.
E-mail address: venkata@wyeth.com (A.M. Venkatesan).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.093

A. M. Venkatesan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 824–827
825
R2
N
H
(CH2)n
H
N
N
(CH2)n
O
OAr
N
2
N
H
H
R2
R
1
N
OAr
O
N
N
N
O
R1
R4
R2
R3
N
H
N
H
N
H
3
4
5
Figure 1.
structure–activity relationship (SAR), we replaced the benzoxazine
portion of 4 with benzofuran moiety. We herein report the syntheses
and SAR of this series 5 of dual-acting compounds.
was carried out using acetic anhydride and fused sodium acetate
in boiling acetic acid; subsequent conversion to the ketone deriva-
tives 13a–f was accomplished by boiling 12a–f in 1N. HCl. Horner–
Emmon’s reaction of 13a–f using (carbethoxymethylene)triphenyl-
phosphorane or (carbethoxyethylidene)triphenylphosphorane in
boiling toluene gave the ester derivatives 14a–f, which were con-
verted to 15a–f using LiAlH4. The alcohol derivatives were con-
verted to their corresponding iodide (16a–f) using the I2/
imidazole/Ph3P procedure. Some derivatives of 15a–f were also
converted to their respective tosylates using p-toluenesulfonyl
chloride/pyridine at 0 °C. The proton NMR and ESMS spectra con-
firmed the structures of all newly prepared compounds. Analogues
43–45 were tested as racemic mixtures.
The
3-{1-[2-(1-benzofuran-3-yl)alkyl]-1,2,3,6-tetrahydro-4-
pyridinyl}-1H-substituted indole 5 were prepared by reacting the
appropriately substituted benzofuran-3-yl-ethyl iodide 6 or the
tosylate 7 with the corresponding substituted or unsubstituted
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole derivative 8a–e in
DMSO at 150 °C in the presence of Hunig’s base (Scheme 1). The
intermediates 8a–e were prepared according to literature proce-
dure,14 while the 3-alkyl-benzofuran derivatives 6a–f were pre-
pared starting from the commercially available substituted
salicyclic acid derivatives as depicted in Scheme 2. The salicyclic
acids were esterified to their corresponding methyl esters 9a–f.
Reaction of 9a–f with bromoethyl acetate in the presence of potas-
sium carbonate in refluxing acetone yielded 10a–f in almost quan-
titative yields. The diesters 10a–f were hydrolyzed to the diacids
11a–f using sodium hydroxide. Cyclization to intermediate 12a–f
The
3-{1-[2-(1-benzofuran-3-yl)alkyl]-1,2,3,6-tetrahydro-4-
pyridinyl}-1H-substituted indole derivatives 17–45 were tested
in vitro to determine affinity for the 5-HT1A receptor and 5-HT
transporter (5-HT-T). Human 5-HT1A (h-5-HT1A) receptor binding
affinity was determined by the displacement of [3H]-8-OH-DPAT
from human 5-HT1A receptors stably transfected into CHO cells
according to Dunlop et al.15 Assessment of the functional activity
at the 5-HT1A receptor for the most active compounds was deter-
mined using a [35S]GTP S assay.16 A protocol similar to that of
c
NH
Cheetham et al.17 was used to determine rat 5-HT transporter
affinity (r5-HT-T). Biological data for all the 3-{1-[2-(1-benzofu-
ran-3-yl)alkyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-substituted in-
dole derivatives 17–45 are presented in Table 1.
R5
R1
X
+
R2
R3
R
O
N
H
Thus benzofuran-3-yl-ethyl iodide 16a (R = H) was initially re-
acted with 8a (R1 to R4 = H) to form 17 (Table 1) a compound with
potent 5HT-T affinity with moderate 5-HT1A affinity. This initial re-
sult encouraged us to probe the SAR more systematically. When
R = H, introduction of 5-cyano 20, 5-fluoro 21 or 7-ethyl 18 into
the 1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole was proved to be
detrimental to both transporter and 5-HT1A receptor affinity. How-
ever, the 6-F derivative 19 gave potent transporter activity without
increasing the 5-HT1A receptor affinity. Similarly, when R = 5-Cl
25–27 or 6-Cl 22–24 in the benzofuran portion the 5-HT1A acitivity
was not improved. Replacement of the 5-Cl in the benzofuran por-
tion of the molecule with 5-F gave potent transporter compounds
28–30 that still had moderate to poor 5-HT1A activity. The effect of
an electron releasing group (–OMe) in the benzofuran was investi-
gated. As can be seen from Table 1, the introduction of the methoxy
group at the 5 and 6-position of the benzofuran gave compounds
31–38 with generally good transporter activity, but poor to moder-
R4
6: X= I
7: X= -OTs
R5 is H or Me
8a-e
8a R1to R4 =H
8b R1 to R3 =H; R4 = Et
8c R1,R2,R4 =H; R3 =F
8d R1, R3, R4 =H; R2 =CN
8e R1,R3, R4 =H; R2 =F
R1
a
R5
N
R2
R
O
N
H
R3
R4
17-45
Scheme 1. General method to prepare 17–45. Reagents and conditions: (a) DMSO,
Hunig’s base, 150 °C, 4 h.

826
A. M. Venkatesan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 824–827
R
R
R
COOCH3
OH
COOCH3
COOH
O
a
b
OMe
OH
O
O
11a-f
O
9a-f
10a-f
c
R5
O
OAc
OEt
R
R
R
e
d
O
O
O
O
14a-f
13a-f
12a-f
f
R5
R5
OH
X
R
R
g
O
O
16a-f, X = I or Ts
15a-f
9a =
16a-f
R5 = H or Me
methyl 2-hydroxybenzoate
9d = methyl 5-fluoro-2-hydroxybenzoate
9e = methyl 5-methoxy-2-hydroxybenzoate
9f = methyl 4-methoxy-2-hydroxybenzoate
9b =methyl 4-chloro-2-hydroxybenzoate
9c = methyl 5-chloro-2-hydroxybenzoate
Scheme 2. General method to prepare 16a–f. Reagents and conditions: (a) BrCH2COOMe; K2CO3, acetone, reflux, 6 h; (b) NaOH,EtOH, THF, reflux, 24 h; (c) (CH3CO)2O fused
CH3COONa, CH3COOH, reflux/3 h; (d) 1 N HCl, MeOH, reflux, 1 h; (e) Ph3P@C(R5)COOEt, toluene, reflux, 24 h (R = H or Me); (f) LiAlH4, THF, 0 °C: (g) when X = OTs, p-toluene
sulfonylchloride, pyridine, 0 °C, 24 h: when X = I, I2, imidazole, PPh3, THF, rt, 4 h.
Table 1
In vitro data for compounds 17–44
R1
R4
R1
N
N
R2
R3
R2
R3
O
R
O
R
N
H
N
H
R4
17-42
43-45
Compd #
R
R1
R2
R3
R4
h-5-HT1A (Ki nM or% inh)
r-5-HT-T (Ki nM or% inh)
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CN
F
H
F
H
H
F
H
H
CN
F
H
F
H
H
H
F
H
CN
H
H
F
H
H
F
H
H
H
H
F
H
H
F
H
H
H
H
H
F
H
H
H
F
H
H
F
H
H
H
H
F
H
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
H
H
H
H
H
H
H
H
H
H
H
36.1
1%*
1.33
156
56.3
42%*
248.0
49%*
30%*
45%*
29%*
46%*
6%*
190.0
41.5
300.0
23%*
44%*
8%*
2.55
90.0
14.0
12.0
300.0
3.54
14.0
15.0
3.00
3.14
4.13
9.25
11.0
54.0
5.50
41.0
3.36
3.63
1.20
3.36
2.85
0.76
3.17
3.24
3.98
13.0
1.97
H
6-Cl
6-Cl
6-Cl
5-Cl
5-Cl
5-Cl
5-F
5-F
5-F
5-OMe
5-OMe
5-OMe
5-OMe
6-OMe
6-OMe
6-OMe
6-OMe
7-OMe
7-OMe
7-OMe
7-OMe
7-OMe
7-OMe
7-OMe
39%*
56.3
66.3
303.0
12.7
8.46
11.0
10.1
5.14
29.2
48%*
48%*
CN
H
F
H
Ki values in nM.
*
% Inhibition at 1 lM.

A. M. Venkatesan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 824–827
827
ate 5-HT1A receptor affinity. The exception was compound 38,
Acknowledgments
which showed good affinity to both targets, (5-HT-T Ki = 3.36 nM;
5-HT1A Ki = 12.7 nM) but subsequently found to be partial agonist
at the 5-HT1A receptor (Imax = 50%). Introduction of the -OMe group
at the 7-position of the benzofuran gave potent compounds 39–42
with both transporter and 5-HT1A affinity. Introduction of 6-F in
the indole moiety 40 afforded a highly potent transporter com-
pound (Ki = 0.76 nM). Moreover, this compound possesses potent
5-HT1A affinity (Ki = 11.0 nM) but functions as a full agonist at
the 5-HT1A receptor (Emax = 100%). Compound 42 has balanced
affinities for the two targets but is a partial 5-HT1A agonist
(Imax = 59%). Introduction of a methyl group in the linker chain of
39 gave compound 43 that has good affinity for the 5-HT trans-
porter and moderate affinity for the 5-HT1A receptor. Introduction
of a fluorine at either the 5- 44 or 6- position 45 of the benzofuran
further decreased the 5-HT1A receptor affinity while having less af-
fect on the transporter affinity.
In this Letter, we have disclosed a series of of novel 3-{1-[2-(1-
benzofuran-3-yl)alkyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-substi-
tuted indole derivatives that generally posses potent affinity for
the 5-HT-T and show good to moderate 5-HT1A affinity. In addition,
structure–activity relationships have been delineated such that
these compounds can have 5-HT1A antagonist functional activity
via the optimization of the R1 and R3 groups in benzofuran and in-
dole nucleus. Most interestingly, analog such as 40 possesses po-
tent 5-HT-T and 5-HT1A affinities. However, this compound
functions as a full 5-HT1A agonist. Further studies concerning
agents that target the 5-HT1A and 5-HT-T receptors will be re-
ported in due course.
The authors thank Drs. Tarek S. Mansour for his support and help-
ful suggestions and useful discussions in the preparation of this
manuscript. The authors thank the members of the Wyeth Chemical
Technologies group for analytical and spectral determination.
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