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

Article abstract of DOI:10.1016/S0960-894X(03)00303-2

A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT_1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinity at the 5-HT_1A receptor and serotonin reuptake inhibition at nanomolar concentrations for dual activities.

Full text of DOI:10.1016/S0960-894X(03)00303-2

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1903–1905
Advances Toward New Antidepressants Beyond SSRIs:
1-Aryloxy-3-piperidinylpropan-2-ols with Dual 5-HT1A Receptor
Antagonism/SSRI Activities. Part 1
Kumiko Takeuchi,* Todd J. Kohn, Nicholas A. Honigschmidt, Vincent P. Rocco,
Patrick G. Spinazze, Daniel J. Koch, 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 17 December 2002; accepted 17 February 2003
Abstract—A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin
reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective
and high affinity at the 5-HT1A receptor and serotonin reuptake inhibition at nanomolar concentrations for dual activities.
# 2003 Elsevier Science Ltd. All rights reserved.
Selective serotonin (5-HT) reuptake inhibitors (SSRIs)
have become a standard treatment in recent years
because of their safety profile and fewer side effects than
the older tricyclic antidepressants. A major drawback of
the now widely prescribed SSRIs is their slow onset of
antidepressant activity. One hypothesis for this latency
is that the initial SSRI-induced increase in extracellular
5-HT activates somatodendritic 5-HT1A autoreceptors,
thus, inhibiting the firing rate of the 5-HT neurons and
limiting the rise in extracellular 5-HT.1À3 With chronic
SSRI treatment it is thought that the autoreceptors
desensitize, allowing the serotonergic neurons to resume
their normal firing rate and enabling extracellular levels
of 5-HT to rise to levels sufficient to achieve anti-
depressant effects. Co-administration of a 5-HT1A
receptor antagonist and an SSRI has been shown to
serotonin reuptake inhibition (Fig. 1). We identified
fused bicyclic aryl-substituted piperidines as an essential
pharmacophore for 5-HT reuptake inhibition. Incor-
poration of an aryloxy group with a propanol chain
linker which exhibited affinity at the 5-HT1A receptor
induced a combined 5-HT1A/SSRI activity in one
single molecule. We report here the synthesis and
initial structure–activity relationship (SAR) study of 1
-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiper-
idinyl)propan-2-ols that exhibited selective and potent
dual activities of 5-HT1A receptor antagonism and 5-HT
reuptake inhibition.
Scheme 1 shows the synthesis of the target compounds.
A substituted benzo[b]thiophene 1 in THF was depro-
tonated with n-butyllithium to add to N-Boc-protected
accelerate antidepressant effects by several groups.4À7
A
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 emerged.8,9
In the course of our efforts to develop more efficacious
antidepressants with a faster onset of action, we dis-
covered a series of 1-aryloxy-3-piperidinylpropan-2-ols
possessing dual 5-HT1A receptor antagonism and
*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)00303-2

1904
K. Takeuchi et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1903–1905
Scheme 1. Synthesis of 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols.
4-piperidone. Dehydration of 2 with trifluoroacetic acid
in CH2Cl2 followed by hydrogenation of the resultant
olefin in EtOH/CF3CH2OH afforded the 4-benzo[b]-
thiophenylpiperidine 3. Coupling of 3 with 4-oxira-
nylmethoxy-1H-indole in MeOH at reflux then provided
1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiper-
idinyl)propan-2-ol derivatives 4–32.
receptor and 16.75 nM at the 5-HT reuptake site). Table 1
shows the effect of electron donating group (EDG) on
the binding affinity and in vitro functional activity of
the 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpi-
peridinyl)propan-2-ols. Regiochemistry and the size of
the EDG-substituents affected both the 5-HT1A receptor
affinity and reuptake inhibition, but more profoundly
the latter, as compared to the unsubstituted 4. Sub-
stitution at the 4-position of benzo[b]thiophene ring was
most preferred (5 and 14). A bigger substituent such as
isopropoxy (9 and 10) or polar hydroxy group (11 and
12) reduced the biological activity particularly at the
reuptake site. Disubstitution (16 and 17) was also detri-
mental to the dual activities, compared to the unsub-
stituted analogue 4.
Compounds were evaluated in vitro to determine their
affinity at the 5-HT1A receptor and 5-HT transporter
sites as well as their functional activity as an agonist or
antagonist, according to the previously described meth-
ods.10À12 Biological activities of the compounds
explored are shown in Tables 1–3. The compound 4 (R,
X=H) exhibited excellent dual activities in low nano-
molar concentrations (Ki=3.70 nM at the 5-HT1A
Table 2 shows the effect of electron withdrawing group
(EWG) on the binding affinity and in vitro functional
activity of the series. Overall, the EWG-substituents
provided potent and more balanced dual activities than
the EDG substituents except the compounds 22 and 24.
Table 1. Effect of EDG-substituted 1-(1H-indol-4-yloxy)-3-(4-ben-
zo[b]thiophen-2-ylpiperidinyl)propan-2-ols
Table 2. Effect of EWG-substituted 1-(1H-indol-4-yloxy)-3-(4-ben-
zo[b]thiophen-2-ylpiperidinyl)propan-2-ols
Compd
X
5-HT1A
Ki (nM)a
Paroxetine 5-HT1A GTPgS
Ki (nM)b
Emax (%)c
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H
3.70Æ0.61 16.75Æ2.13
1.89Æ0.73 12.63Æ0.50
12.26
7.47
ND
4.92
9.32
ND
ND
ND
12.52
ND
4-OMe
5-OMe
6-OMe
7-OMe
4-OiPr
6-OiPr
6-OH
7-OH
3-Me
4-Me
6-Me
4,6-diMe
1.44Æ0.27
—
3.13Æ1.48 68.67Æ15.43
6.13Æ1.94 94.32Æ16.21
Compd
X
5-HT1A
Ki (nM)a
Paroxetine
Ki (nM)b
GTPgS
Emax (%)c
7.45Æ2.15
19.85Æ1.35
3.09Æ0.85
—
—
—
4
H
4-F
5-F
6-F
3.70Æ0.61
6.79Æ0.27
29.40Æ7.90
9.31Æ1.29
9.12Æ0.20
7.21Æ0.85
7.64Æ1.54
5.17Æ0.42
16.75Æ2.13
15.89Æ0.20
11.81Æ7.16
1.99Æ0.14
15.63Æ4.88
105.14Æ78.09
13.96Æ0.00
—
12.26
11.17
13.23
11.65
ND
10.97
ND
ND
18
19
20
21
22
23
24
7.12Æ1.36 37.16Æ4.46
6.28Æ2.44 24.05Æ1.08
4.70Æ0.64 3.69Æ0.99
12.66Æ3.89 50.49Æ8.72
4-Cl
5-Cl
6-Cl
5-F-3-Me
16.99
13.85
ND
—
—
—
6-OMe-3-Me 6.07Æ1.80
ND
aBinding affinity at 5-HT1A receptors labeled with [3H]-8-OH-DPAT
(n ꢀ2).10
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 —denotes <50% inhibition at 100 nM, no Ki was generated.
cMaximal response of the compound as a result of 5-HT1A receptor-
mediated stimulation of [35S]GTPgS binding.12 ND denotes ‘not
determined’ due to the weak binding affinity at either one or both sites.
bAffinity at the 5-HT reuptake site labeled with [3H]-paroxetine
(n ꢀ2).11 —denotes <50% inhibition at 100 nM, no Ki was generated.
cMaximal response of the compound as a result of 5-HT1A receptor-
mediated stimulation of [35S]GTPgS binding.12 ND denotes ‘not
determined’ due to the weak binding affinity at either one or both sites.

K. Takeuchi et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1903–1905
1905
Table 3. Effect of 2-methylindole
properties. By this sensitive measure, the compounds of
this class appeared as very weak partial agonists (shown
in the tables as the Emax values expressed as a percen-
tage of the maximal activity of 5-HT). It was found that
compounds having 15% or less maximal stimulation of
the 5-HT1A receptor measured in the in vitro GTPgS
binding assay behaved only as functional antagonists in
vivo, with no measurable agonist character (unpub-
lished observations). Moreover, these compounds were
tested against other cloned human 5-HT receptor sub-
types in the radioligand binding assays and found to be
inactive or very weak at other 5-HT receptors.
Compd
X
5-HT1A
Ki (nM)a
Paroxetine
Ki (nM)b
5-HT1A GTPgS
Emax (%)c
25
26
27
28
29
30
31
32
4-OMe
4-Me
6-Me
4.83Æ0.80 51.16Æ12.93
10.40Æ2.81 17.35Æ1.26
9.05
12.09
ND
13.38
11.62
12.06
12.61
ND
In conclusion, we have identified potent and selective
dual acting 5-HT1A/SSRIs in a single chemical entity.
Further SAR exploration to improve the overall biolo-
gical activity profiles will be reported in due course.
22.60Æ2.30
—
4,6-di-Me 27.83Æ7.05 52.13Æ4.76
4-F
5-F
6-F
5-Cl
14.15Æ2.55 34.17Æ4.71
7.50Æ1.14 5.27Æ0.25
15.35Æ1.85 11.27Æ0.31
60.63Æ7.58
—
Acknowledgements
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 —denotes <50% inhibition at 100 nM, no Ki was generated.
cMaximal response of the compound as a result of 5-HT1A receptor-
mediated stimulation of [35S]GTPgS binding.12 ND denotes ‘not
determined’ due to the weak binding affinity at either one or both sites.
We thank scientists at Synaptic Pharmaceutical Cor-
poration for the 5-HT receptor biding assay data gen-
eration.
References and Notes
Regiochemistry or the size of the EWG-substituents did
not affect the binding affinity and in vitro functional
activity as profoundly as the EDG-substituents did,
with the exception of substituents at the 5-position of
benzo[b]thiophene being less favored especially at the
5-HT reuptake site (22 and 24). Anomaly with another
5-substituted benzo[b]thiophene compound 19 with
fluorine in this case was that it was 3- to 8-fold less
potent at the 5-HT1A receptor site than other EWG-
substituted compounds, though still showing respect-
able dual activities. Inactive reuptake inhibition of the
compound 24 could also be due to the disubstitution as
seen in the EDG-substituted cases (8 and 9).
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These compounds were also studied for their functional
activity at the 5-HT1A receptor in an in vitro GTPgS
binding assay to determine their agonist/antagonist