Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 2

Article abstract of DOI:10.1016/S0960-894X(03)00392-5

Potent 5-HT1A/SSRIs at low nanomolar and subnanomolar concentrations were identified in a series of 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols. Incorporation of an α-Me group in the piperidine ring with its specific stereochemistry enhanced binding affinity at the 5-HT reuptake site and in vitro 5-HT_1A antagonist functional activity.

Full text of DOI:10.1016/S0960-894X(03)00392-5

Bioorganic & Medicinal Chemistry Letters 13 (2003) 2393–2397
Advances Toward New Antidepressants Beyond SSRIs:
1-Aryloxy-3-piperidinylpropan-2-ols with Dual 5-HT1A Receptor
Antagonism/SSRI Activities. Part 2
Kumiko Takeuchi,* Todd J. Kohn, Nicholas A. Honigschmidt, Vincent P. Rocco,
Patrick G. Spinazze, Daniel J. Koch, Steven T. Atkinson, Larry W. Hertel,
David L. Nelson, D. Bradley Wainscott, Laura J. Ahmad, Janice Shaw,
Penny G. Threlkeld and David T. Wong
Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA
Received 28 February 2003; accepted 7 April 2003
Abstract—Potent 5-HT1A/SSRIs at low nanomolar and subnanomolar concentrations were identified in a series of 1-(1H-indol-4-
yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols. Incorporation of an a-Me group in the piperidine ring with its specific
stereochemistry enhanced binding affinity at the 5-HT reuptake site and in vitro 5-HT1A antagonist functional activity.
# 2003 Elsevier Science Ltd. All rights reserved.
Introduction of selective serotonin (5-HT) reuptake
inhibitors (SSRIs) as antidepressants has revolutionized
the treatment of depression. Not only have SSRIs
become a standard treatment for depression, but they
have also widened recognition of depression as a trea-
table disease among medical professionals and the gen-
eral population. Depression has now been recognized as
a debilitating disease with an overwhelming economic
liability to society. A major drawback for the treatment
of depression by the current SSRIs is the delayed onset
of therapeutic benefit.1,2 More recent efforts in devel-
oping newer antidepressants are targeted for a fast act-
ing agent in a single molecule via a mechanism-based
combination therapy. One such approach has stemmed
from reports by several groups that co-administration of a
5-HT1A receptor antagonist and an SSRI has been shown
to accelerate antidepressant effects.3À5 The concept of
developing a dual-acting agent blocking both the 5-HT1A
receptor and the 5-HT reuptake sites in a single molecule
(5-HT1A/SSRI) has been proposed by us and others.6À9
antagonism and serotonin reuptake inhibition (Fig. 1).6
In this report we describe a structure–activity relation-
ship (SAR) study focusing on the piperidine ring of
1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiper-
idinyl)propan-2-ols in order to optimize the dual activ-
ity for 5-HT1A receptor antagonism and 5-HT reuptake
inhibition in the development of more efficacious anti-
depressants with a faster onset of action (Fig. 2).
We first explored the effects of a methyl substituent
alpha to the piperidine nitrogen (R1=Me and R2=H)
in Figure 2. Scheme 1 shows the synthesis of target
compounds, similar to what we have already reported.6
A substituted benzo[b]thiophene 1 was deprotonated
with alkyllithium reagent to add to N-Boc protected
Previously we reported a series of 1-aryloxy-3-piper-
idinylpropan-2-ols possessing dual 5-HT1A receptor
*Corresponding author. Tel.: +1-317-276-6771; fax: +1-317-433-
0715; e-mail: ktak@lilly.com
Figure 1. General structure of 1-aryloxy-3-piperidinylpropan-2-ols,
new 5-HT1A/SSRIs.
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00392-5

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K. Takeuchi et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2393–2397
Scheme 1. Synthesis of 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-yl-2-methylpiperidinyl)propan-2-ols.
Tables 1–3 show the results of biological assays on these
molecules. Affinities at the 5-HT1A receptor and sero-
tonin transporter were measured using standard radio-
ligand-binding assays.10,11 Functional activity at the 5-
HT1A receptor was measured in vitro by the human
cloned 5-HT1A receptor-mediated stimulation of
[35S]GTPgS binding to G proteins.12 Compounds were
first tested for potential agonist activity using a high
concentration (1 mM). As can be seen in Tables 1–4, all
compounds produced less than a 10% stimulation of
[35S]GTPgS binding compared to the maximal stimula-
tion produced by the endogenous agonist 5-HT. To
confirm 5-HT1A receptor antagonism the compounds
were evaluated for their ability to inhibit [35S]GTPgS
binding that was induced by 5-HT. Tables 1–4 show
that tested compounds were able to inhibit the effects of
5-HT down to a level of 10% or less of that produced
by 5-HT. Ki values calculated from these functional
Figure 2. SAR study on 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-
2-ylpiperidinyl)propan-2-ols.
(Æ)-2-methyl-4-piperidone. Dehydration of 2 with TFA
followed by hydrogenation of the resultant olefin affor-
ded the chromatographically separable (cis)- and (trans)
-4 - (benzo[b]thiophen -2 - yl) - 2 -methylpiperidine inter-
mediates 3. Reaction with indolyl glycidyl ether 4 then
yielded four diastereomeric isomers of the target mole-
cules 5–8 that were isolated by flash chromatography.13
Table 1. SAR of 2-methylpiperidine: effects of ring stereochemistry
Compd
X
Isomer
5-HT1A
Ki (nM)a
Paroxetine
Ki (nM)b
GTPgS
Inhibition of 5-HT-stimulated GTPgS binding
binding % Stimc
Ki (nM)d
Emin (%)e
5a
6a
7a
8a
5b
6b
7b
8b
4-OMe
4-OMe
4-OMe
4-OMe
5-F
5-F
5-F
5-F
1 (2R,4R)
2 (2S,4S)
3 (2S,4R)
4 (2R,4S)
1 (2R,4R)
2 (2S,4S)
3 (2S,4R)
4 (2R,4S)
2.76Æ0.02
14.45Æ1.55
3.64Æ0.13
8.47Æ2.03
8.77Æ2.13
36.80Æ0.80
6.40Æ1.06
11.75Æ0.75
14.71Æ1.43
13.59Æ1.12
0.27Æ0.09
1.15Æ0.21
3.53Æ0.61
4.22Æ1.04
0.39Æ0.08
0.99Æ0.22
1.20
1.38
7.77
4.41
7.21
3.24
7.68
6.35
1.80
16.45
2.33
8.37
1.76
16.48
5.67
16.71
2.01
1.43
7.83 (5)
5.97 (8)
10.83
7.87
7.69
10.54
aBinding affinity at 5-HT1A receptors labeled with [3H]-8-OH-DPAT (n ꢀ2).10
bAffinity at the 5-HT reuptake site labeled with [3H]-paroxetine (n ꢀ2).11
cStimulation by a 1 mM compound concentration expressed as a % of the maximal [35S]GTPgS binding induced by 5-HT.
dKi calculated from the inhibition of 5-HT-mediated stimulation of [35S]GTPgS binding.
eDegree of maximal inhibition of 5-HT-mediated stimulation of [35S]GTPgS binding expressed as % of the stimulation produced by 5-HT (300 nM)

K. Takeuchi et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2393–2397
Table 2. Effects of EDG-substituted benzo[b]thiophene derivatives 7
2395
Compd
X
5-HT1A
Ki (nM)a
Paroxetine
Ki (nM)b
GTPgS
Inhibition of 5-HT-stimulated GTPgS binding
binding % Stimc
Ki (nM)d
Emin (%)e
7a
7c
7d
7e
7f
4-OMe
6-OMe
4,5-di-OMe
4-Me
6-Me
3.64Æ0.13
14.49Æ2.76
1.30Æ0.22
6.85Æ1.03
—
0.27Æ0.09
1.10Æ0.29
10.83Æ1.66
0.44Æ0.04
2.24Æ0.14
1.93Æ0.33
7.77
5.26
8.38
8.48
nd
2.33
2.98
0.98
8.75
nd
7.83 (5)
6.67
4.80
4.96
nd
7g
4,6-di-Me
94.90Æ11.50
nd
nd
nd
aBinding affinity at 5-HT1A receptors labeled with [3H]-8-OH-DPAT (n ꢀ2).10 – denotes <50% inhibition at 100 nM, no Ki was generated.
bAffinity at the 5-HT reuptake site labeled with [3H]-paroxetine (n ꢀ2).11
cStimulation by a 1 mM compound concentration expressed as a% of the maximal [35S]GTPgS binding induced by 5-HT.
dKi calculated from the inhibition of 5-HT-mediated stimulation of [35S]GTPgS binding.
eDegree of maximal inhibition of 5-HT-mediated stimulation of [35S]GTPgS binding expressed as % of the stimulation produced by 5-HT (300 nM)
(n=1 unless noted otherwise in parentheses). nd denotes ‘not determined’ due to the weak binding affinity.
Table 3. Effects of EWG-substituted benzo[b]thiophene derivatives 7
Compd
X
5-HT1A
Ki (nM)a
Paroxetine
Ki (nM)b
GTPgS
Inhibition of 5-HT-stimulated GTPgS binding
binding % Stimc
Ki (nM)d
Emin (%)e
7h
7i
7b
7j
7k
7l
7m
7n
7o
H
4-F
5-F
6-F
3.09Æ0.18
13.87Æ4.64
6.40Æ1.06
5.52Æ1.04
21.95Æ4.55
—
8.34Æ1.36
24.85Æ0.65
24.23Æ2.31
0.51Æ0.06
1.16Æ0.15
0.39Æ0.08
0.31Æ0.06
3.47Æ2.20
0.69Æ0.04
0.58Æ0.23
1.10Æ0.42
3.46Æ0.38
6.32
5.37
7.68
5.32
2.66
nd
3.97
8.49
nd
3.28
4.88
5.67
7.45
4.23
nd
5.26
11.66
nd
7.50
7.44
7.69
9.00
6.80
nd
6.81
7.99
nd
7-F
4-Cl
5-Cl
6-Cl
4-CF3
aBinding affinity at 5-HT1A receptors labeled with [3H]-8-OH-DPAT (n ꢀ2).10 – denotes <50% inhibition at 100 nM, no Ki was generated.
bAffinity at the 5-HT reuptake site labeled with [3H]-paroxetine (n ꢀ2).11
cStimulation by a 1 mM compound concentration expressed as a % of the maximal [35S]GTPgS binding induced by 5-HT.
dKi calculated from the inhibition of 5-HT-mediated stimulation of [35S]GTPgS binding.
eDegree of maximal inhibition of 5-HT-mediated stimulation of [35S]GTPgS binding expressed as % of the stimulation produced by 5-HT (300 nM);
(n=1). nd denotes ‘not determined’ due to the weak binding affinity.
inhibition curves were generally in good agreement with
the Ki values determined from the radioligand-binding
assays.
2 (2S,4S) in general (Scheme 1), though only two
representative examples are shown in Table 1. Dual
activities improved overall, compared to the des-
methylpiperidine series reported earlier.6 In particular
this series exhibited excellent 5-HT reuptake inhibition
and improved the 5-HT1A antagonism functional activ-
ity. Both electron donating (EDG) and withdrawing
(EWG) substituents (Tables 2 and 3) were well toler-
ated, which might provide metabolic advantages in the
in vivo profile of this series of compounds. There was a
We found interesting stereochemical influences of the
four isomers on the binding affinity and in vitro func-
tional activity (Table 1). There was a stereochemical
preference on both 5-HT1A receptor antagonism and
5-HT reuptake inhibition in the order of Isomer 3
(2S,4R)>Isomer 4 (2R,4S)>Isomer 1 (2R,4R)>Isomer

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K. Takeuchi et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2393–2397
Table 4. Effects of rigidified stereocenter in the piperidine ring
Compd
X
Isomer
5-HT1A
Ki (nM)a
Paroxetine
Ki (nM)b
GTPgS
Inhibition of 5-HT-stimulated GTPgS binding
binding % Stimc
Ki (nM)d
Emin (%)e
9
10
11
H
OMe
OMe
Unknown
exo
endo
30.55Æ3.75
15.70Æ1.10
—
0.07Æ0.01
1.31Æ0.49
0.17Æ0.04
9.26
7.22
nd
70.08
18.75
nd
9.40
4.02
nd
aBinding affinity at 5-HT1A receptors labeled with [3H]-8-OH-DPAT (n ꢀ2).10 – denotes <50% inhibition at 100 nM, no Ki was generated.
bAffinity at the 5-HT reuptake site labeled with [3H]-paroxetine (n ꢀ2).11
cStimulation by a 1 mM compound concentration expressed as % of the maximal [35S]GTPgS binding induced by 5-HT.
dKi calculated from the inhibition of 5-HT-mediated stimulation of [35S]GTPgS binding.
eDegree of maximal inhibition of 5-HT-mediated stimulation of [35S]GTPgS binding expressed as a% of the stimulation produced by 5-HT
(300 nM). (n=1 unless). nd denotes ‘not determined’ due to the weak binding affinity.
regiochemical preference in the substitution patterns as
seen in the des-methyl series:6 preferences in EDG at 4-
position (Table 2) and EWG at 5-position (Table 3) of
benzo[b]thiophene. Another striking effect of 2-methyl-
piperidine was that di-substitution in the benzo[b]thio-
phene ring was well tolerated (7d, 7g), especially in the
5-HT reuptake inhibition, in contrast to des-methyl
series,6 which were inactive.
acting and relating to the stereochemistry of the piper-
idine middle ring of the molecule.
In conclusion, we have identified potent 5-HT1A/SSRIs
in a series of 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thio-
phen-2-ylpiperidinyl)propan-2-ols. Incorporation of an
a-Me group in the piperidine ring with its specific ste-
reochemistry enhanced binding affinity at the 5-HT
reuptake site and in vitro 5-HT1A antagonist functional
activity. Further optimization of pharmacological pro-
files of this series of compounds will be reported in due
course.
With the stereochemical influence of the methyl sub-
stituent on the piperidine ring observed, we further
explored the effects of di-substitution in the piperidine
ring. The purposes of these substituents were (1) to
remove the stereogenic center at the 2-position and (2)
to fixate the piperidine ring. 2,2-gem-Dimethylpiper-
idines (Fig. 3) were inactive in both binding affinity
assays at the 5-HT1A receptor and 5-HT reuptake site.
Acknowledgements
We thank scientists at Synaptic Pharmaceutical Cor-
poration for the 5-HT receptor biding assay data
generation.
Interesting results were observed with rigidified piper-
idine, namely tropane derivatives (Table 4). The com-
pound
9
without any substituent on the
References and Notes
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take inhibitor with somewhat modest 5-HT1A receptor
affinity. Two stereoisomers of the tropane ring com-
pounds14 showed distinctive differences in the 5-HT1A
receptor affinity. The exo-isomer 10 showed respectable
affinity at the 5-HT1A receptor, whereas the endo-isomer
11 was inactive. These results suggest the importance of
a certain conformational bias at the receptor site inter-
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Figure 3. 2,2-Dimethylpiperidine derivatives.

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10. Affinities of compounds at the 5-HT1A receptor were
determined by Synaptic Pharmaceutical Corp. using cell lines
expressing the human 5-HT1A receptor with standard assay
techniques as previously described: Weinshank, R. L.; Zgom-
bick, J. M.; Macchi, M. J.; Brancheck, T. A.; Hartig, P. R.
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but adapted to a scintillation proximity assay (SPA) format.
See: Rasmussen, K.; Calligaro, D. O.; Czachura, J. F.; Dresh-
field-Ahmad, L. J.; Evans, D. C.; Hemrick-Luecke, S. K.;
Kallman, M. J.; Kendrick, W. T.; Leander, J. D.; Nelson,
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13. Absolute stereochemistry of one of the ‘Isomer 3’ was
determined by a single crystal X-ray determination, and then
the relative stereochemistry of other three isomers were deter-
1
mined by H NMR.
14. 3 - (4 - Methoxybenzo[b]thiophen - 2 - yl) - 8 - azabicyclo
[3.2.1]octane was prepared from N-carboethoxy-4-tropinone
and its stereochemistry was determined by the 1H NMR,
COSY, ROESY or 1D TOCSY, and eHSQC experiments.
Details of the stereoselective synthesis of each isomer will be
reported elsewhere.