1-(2-Phenoxyphenyl)methanamines: SAR for dual serotonin/noradrenaline reuptake inhibition, metabolic stability and hERG affinity

Article abstract of DOI:10.1016/j.bmcl.2007.11.080

A novel series of 1-(2-phenoxyphenyl)methanamines is disclosed, which possess selective dual 5-HT and NA reuptake pharmacology. Analogues with good human in vitro metabolic stability, hERG selectivity and passive membrane permeability were identified.

Full text of DOI:10.1016/j.bmcl.2007.11.080

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 596–599
1-(2-Phenoxyphenyl)methanamines: SAR for dual
serotonin/noradrenaline reuptake inhibition, metabolic
stability and hERG affinity
Gavin A. Whitlock,* Julian Blagg and Paul V. Fish
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
Received 1 November 2007; revised 19 November 2007; accepted 19 November 2007
Available online 28 November 2007
Abstract—A novel series of 1-(2-phenoxyphenyl)methanamines is disclosed, which possess selective dual 5-HT and NA reuptake
pharmacology. Analogues with good human in vitro metabolic stability, hERG selectivity and passive membrane permeability were
identified.
Ó 2007 Elsevier Ltd. All rights reserved.
We recently disclosed a number of novel series with dual
serotonin (5-HT) and noradrenaline (NA) reuptake inhi-
bition (SNRI), exemplified by piperazine 11 and amino-
pyrrolidine 2.2 This dual pharmacology mechanism has
been shown to be an attractive approach for the treat-
ment of a number of diseases, such as depression,3,4 neu-
ropathic pain5,6 and urinary incontinence.7,8
H
N
O
NH
N
N
1
2
Me
OEt
O
Me
As part of a multi-template approach towards dual 5-
HT/NA reuptake inhibitors, we investigated other scaf-
folds which were structurally diverse from 1 and 2
(Fig. 1). Recent disclosures have shown that diphenyle-
ther structures such as ODAM 3 and ADAM 4 have po-
tent monoamine reuptake activity.9 We now wish to
report our results on this series 5, focussing on SAR
for dual SNRI pharmacology along with an assessment
of drug-like properties based on in vitro human meta-
bolic stability and hERG affinity.
Me
NMe2
R
N
R2
Ring A
R3
O
3 R = CH2OH ODAM
4 R = NH2 ADAM
Ring B
5
R1
I
Figure 1. Recently disclosed SNRI’s and structure of diphenylether
template.
The target compounds were prepared in a 2-step se-
quence (Scheme 1). 2-Fluorobenzaldehydes 6 were dis-
placed with phenols 7, and then reductive amination
conditions were employed to introduce the benzylic
amine. This parallel synthesis approach allowed rapid
evaluation of SAR for dual activity in the A and B rings.
The tertiary amine lead 9 showed weak 5-HT activity
but encouraging levels of NA potency. We then assessed
the effect of substitution on the B ring. 2-Cl analogue 10
gave selective NA activity, the 3-Cl isomer 11 gave weak
broad-spectrum activity and the 4-Cl isomer 12 was
selective for 5-HT reuptake inhibition. Combination of
2 and 4-substitution (analogue 13) delivered excellent
dual 5-HT and NA activity with encouraging selectivity
over dopamine (DA) reuptake. Having identified a sub-
stitution pattern for potent SNRI activity, we then ex-
panded the SAR further. 2-OMe and 2-F groups were
Keywords: Serotonin; Noradrenaline; Monoamine reuptake inhibitor;
Metabolic stability; hERG affinity.
*
Corresponding author. Tel.: +44 1304 649174; fax: +44 1304
651987; e-mail: gavin.whitlock@pfizer.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.080

G. A. Whitlock et al. / Bioorg. Med. Chem. Lett. 18 (2008) 596–599
597
O
R2
R2
O
F
OH
Me
R2
H
N
(a)
(b)
H
R3
+
O
R1
O
or (C)
6
7
8
9-36
R1
R1
Scheme 1. Synthesis of 1-(2-phenoxyphenyl)methanamine target compounds. Reagents and conditions: (a) K2CO3, DMF, 100 °C; (b) R3 = H;
i—methylamine in ethanol; ii—NaBH4, EtOH, rt; R3 = Me, dimethylamine in ethanol, NaBH(OAc)3, THF, rt.
NHMe
O
S
R2
Me
Me
R1
N
N
H2N
H
H
O
O
O
+
OMe
Cl
Cl
Cl
Structure in Blue
Cl
R2 = Polar group
Structure in Green
Figure 2. In silico overlap of tetrahydronaphthalene SSRIs with compound 17.
Table 1. In vitro inhibition of monoamine reuptake,a,b in vitro metabolic stability,c hERG channel affinityd and clogP calculationse for compounds
9–22
Me
N
R3
O
R1
Compound R1
R3
5-HT IC50 (nM) NA IC50 (nM) DA IC50 (nM) HLM Clint ll/min/mg hERG Ki (nM) clogP
1
—
—
—
—
13
9
16
7
>4000
727
NT
—
<7
—
4.2
2.4
4.1
4.6
4.8
4.6
5.3
4.7
4.7
4.5
2
>7500
NT
NT
9
H
2-Cl
Me 660
Me 282
Me 238
70
15
82
256
11
21
46
14
NT
186
NT
NT
223
NT
219
45
10
11
12
13
14
15
16
2730
194
3-Cl
4-Cl
NT
NT
Me
Me
Me
Me
18
4
124
195
2,4 di-Cl
2-F 4-Cl
2-Cl 4-F
>7500
NT
NT
6
421
32
6
2130
3780
2-OMe 4-Cl Me
>7500
17
18
19
20
21
22
2-OMe 4-Cl
2,4 di-Cl
H
H
H
H
H
H
13
56
78
42
19,600
506
421
9
4380
NT
4.0
4.8
4.8
4.2
4.3
4.2
NT
20
2-Me 4-Cl
2-Cl 4-F
2-F 4-Cl
18
22
NT
NT
NT
73
300
429
157
6510
NT
NT
22
5932
NT
2-Cl 4-OMe
22
5950
NT
NT denotes not tested.
a See Ref. 10 for description of assay conditions.
b Monoamine reuptake IC50 values are geometric means of at least three experiments.
c Minimun measurable clearance was 7 ll/min/mg protein.
d Ki values are geometric means of two experiments.
e clogP values calculated using BioByte clogP software.
well tolerated, in particular the 2-OMe 4-Cl compound
16 retained SNRI potency and increased selectivity over
DA reuptake.
All of the N,N-dimethyl amines suffered from poor met-
abolic stability,11 so we then investigated the potency of
the more polar secondary amines. In all cases there was

598
G. A. Whitlock et al. / Bioorg. Med. Chem. Lett. 18 (2008) 596–599
Figure 4. Plot of clogP against hERG activity. Squares coloured by
clogP.
Figure 3. Plot of clogP against HLM Clint. Squares coloured by
clogP.
a drop in 5-HT/NA potency, but analogues 17, 18 and
19 retained interesting levels of SNRI activity with mod-
erate to good DA selectivity and improved metabolic
stability. A number of these compounds were also as-
sessed for their affinity for the hERG channel, and we
were pleased to see weak hERG inhibition across both
the secondary and tertiary amines.
We then decided to introduce a polar group onto ring A
as a strategy for reducing lipophilicity further. In silico
generated overlaps with a series of tetrahydro-naphtha-
lene SSRIs,12 indicated that polar groups may be toler-
ated in this area of the molecule (Fig. 2). Based on this
overlap we thought that 5-HT reuptake inhibition
Table 2. In vitro inhibition of monoamine reuptake,a,b human microsomal stability,c hERG channel activity,d clogPe and Papp values for
compounds 23–36
R2
CH3
N
H
O
R1
Cl
Compound
R1
R2
5-HT
IC50 (nM)
NA IC50
(nM)
DA IC50
(nM)
HLM Clint
uL/min/mg
hERG
Ki (nM)
clogP
PAMPA
Papp (10À6cm/sec)
23
24
25
26
OMe
OMe
OMe
OMe
CN
5
12
13
8
>400
62
78
>40000
21000
15700
NT
8
NT
3.5
2.5
2.8
2.5
NT
11
CONH2
CONHMe
CONMe2
>7500
>7500
>7500
8
15
14
15
32
>40000
27
28
29
30
Cl
Cl
Cl
Cl
CN
28
37
13
11
>400
84
38
3010
1210
800
NT
8
2213
>7500
1757
NT
4.2
3.3
3.5
3.3
NT
10
CONH2
CONHMe
CONMe2
O
9
13
NT
14
33
275
O
S
31
Cl
12
17
138
12
1556
3.8
NT
N
32
33
34
Me
Me
Me
CONH2
CONHMe
CONMe2
O
7
14
17
46
26
17
2820
387
8
9
9
3866
>7500
3751
3.3
3.5
3.3
NT
NT
19
172
O
S
35
Me
10
11
25
47
11
8
1590
7250
3.8
3.6
2.7
2.2
N
36
Me
NHSO2Me
16
320
NT denotes not tested.
a See Ref. 10 for description of assay conditions.
b Monoamine reuptake IC50 values are geometric means of at least three experiments.
c Minimun measurable clearance was 7 ll/min/mg protein.
d Ki values are geometric means of two experiments.
e clogP values calculated using BioByte clogP software.

G. A. Whitlock et al. / Bioorg. Med. Chem. Lett. 18 (2008) 596–599
599
would be retained, although it was unclear whether dual
SNRI activity could be achieved.
thank Jackie Kendal, Mark Andrews, David Hepworth,
Alan Stobie and Don Middleton for useful discussions.
A number of polar R2 groups, such as nitriles, amides,
acyclic and cyclic sulfonamides, were investigated with
the B-ring substitution as 2-OMe 4-Cl, 2,4 di-Cl or
2-Me 4-Cl (Table 2). Nitriles 23 and 27 gave poor NA
reuptake activity, whereas amides and sulfonamides
retained good dual activity. The 2-OMe 4-Cl amides 24–
26 had good SNRI potency and much better DA selec-
tivity than the 2,4 di-Cl analogues 28–30 or 2-Me 4-Cl
targets 32–34. The cyclic sultam compounds 31 and 35
were potent 5-HT/NA reuptake inhibitors but selectivity
was eroded in comparison to the amide R2 substituents.
References and notes
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In all cases with a polar R2 substituent, the in vitro hu-
man metabolic stability was good, with no Clint values
higher than 15 ll/ml/mg. This was in contrast to the
metabolic instability observed for the more lipophilic
examples in Table 1, suggesting a relationship between
metabolic stability and lipophilicity. This trend became
clear upon analysis of all the HLM and clogP data from
this series (Fig. 3), with a clogP of less than 4.0 giving
good stability, and a clogP of greater than 4.5 leading
to high metabolic turnover.
We also observed that lipophilicity had some influence
on hERG activity, for example compounds with
clogP < 3.0 all had weak hERG activity. However, at
clogP > 3.0 it appeared that activity was more related
to structure (Fig. 4), with hERG inactives spanning a
wide clogP range.
8. Steers, W. D.; Herschorn, S.; Kreder, K. J.; Moore, K.;
Strohbehn, K.; Yalcin, I.; Bump, R. C. BJU Int. 2007, 100,
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10. The assays were a modification of those described by
Blakely et al. Anal. Biochem. 1991, 194, 302, HEK293
cells expressing a single human amine transporter protein
(7500 cells/well in Millipore 96-well filter bottom plates)
were pre-incubated at 25 °C for 5 min with assay buffer
containing vehicle (DMSO in water) or test compound.
Uptake of neurotransmitter into the cells was initiated by
the addition of tritiated 5-HT (50 nM), NA (200 nM) or
DA (200 nM) substrates, the samples were shaken in an
incubator at 25 °C for 5 min (5-HT, DA) or 15 min (NA).
The assays were stopped by an ice-cold buffer wash
followed by filtration. The filters were then dried before
measuring the amount of radioactivity taken up into the
cells by scintillation counting. Potency of test compounds
was quantified as IC50 values, that is, concentration
required to inhibit the specific uptake of radiolabelled
substrate into the cells by 50% relative to maximum
(vehicle only) over a 10-point dose response range. A
minimum of three experiments were made.
We also determined whether addition of polar substitu-
ents would adversely affect membrane permeability. In
vitro PAMPA screening13 (Table 2) showed examples
24–26 had good passive permeability, in contrast to
the sulfonamides 35 and 36, which were poorly fluxed.
In summary, we have described a novel series of dual 5-
HT/NA reuptake inhibitors with excellent selectivity
over DA reuptake activity. B-ring SAR showed that a
2,4-disubstitution pattern was optimal for achieving
dual pharmacology. 2-OMe 4-Cl compounds 17, 24, 25
and 26 combine excellent pharmacological properties
along with good in vitro human metabolic stability,
hERG selectivity and passive membrane permeability.
By using correlations between clogP and either HLM
stability or hERG affinity we were able to determine
that metabolic turnover was primarily lipophilicity dri-
ven, whereas hERG affinity appeared to be more influ-
enced by structure. Further advances in the SAR of
this series will be reported in the near future.
11. Metabolite identification studies demonstrated that N-
demethylation to the secondary amine was the major route
of metabolism.
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Jessiman, A.; Johnson, P. S.; MacKenny, M.; Pitcher, M.
J.; Rooker, T.; Stobie, A.; Tang, K.; Morgan, P. Bioorg.
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Acknowledgments
We thank Liz Hopkins, Stephen Phillips, David
Winpenny and Alison Bridgeland for screening data,
and Debbie Lovering, Carol Bains and Kerry Paradow-
ski for compound synthesis. We are also grateful to Ian
Gardner and Peter Bungay for ADME studies. We also