3-(Arylamino)-3-phenylpropan-2-olamines as a new series of dual norepinephrine and serotonin reuptake inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.03.054

A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhib

Full text of DOI:10.1016/j.bmcl.2009.03.054

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2464–2467
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
3-(Arylamino)-3-phenylpropan-2-olamines as a new series of dual
norepinephrine and serotonin reuptake inhibitors
a
a
a
a
An T. Vu a, , Stephen T. Cohn , Eugene A. Terefenko , William J. Moore , Puwen Zhang ,
Paige E. Mahaney a, Eugene J. Trybulski a, Igor Goljer a, Rebecca Dooley a, Jenifer A. Bray b,
Grace H. Johnston b, Jennifer Leiter b, Darlene C. Deecher b
*
a Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
b Women’s Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhi-
bit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin
reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 15 February 2009
Revised 10 March 2009
Accepted 12 March 2009
Available online 18 March 2009
Keywords:
3-(Arylamino)-3-phenylpropan-2-olamines
Serotonin and norepinephrine reuptake
inhibitors
SNRI
Norepinephrine reuptake inhibitors
NRI
Serotonin reuptake inhibitor
SRI
Monoamine reuptake inhibitors
Biogenic monoamine neurotransmitters, specifically serotonin
(5-HT), norepinephrine (NE) and dopamine (DA), play a crucial role
in various central nervous system (CNS) activities, and monoamine
deficiency has been implicated in a variety of CNS disorders.1 One
approach to enhance monoaminergic neurotransmission is to inhi-
bit its reuptake after release into the synaptic cleft. Selective sero-
tonin reuptake inhibitors (SSRI) such as fluoxetine (1), paroxetine
and sertraline have been widely used for the treatment of depres-
sion as well as other neuropsychiatric disorders. In contrast, fewer
selective norepinephrine reuptake inhibitors (NRI) are in clinical
use.2 Atomoxetine (2), a moderately selective NRI, was approved
for the treatment of attention deficit hyperactivity disorder
(ADHD);3 whereas racemic reboxetine (3), a selective NRI, is mar-
keted in Europe for the treatment of major depressive disorder
(MDD).4 In addition, some recent data suggest that these
compounds also have clinical implications in treating chronic pain
disorders such as fibromyalgia and low back pain.5 The S,S-enantio-
mer of reboxetine, a highly selective NRI, is currently in clinical
studies in the US for the treatment of fibromyalgia and diabetic
neuropathy. Furthermore, dual acting serotonin and norepineph-
rine reuptake inhibitors (SNRI) such as venlafaxine (4) and duloxe-
tine (5) have emerged as another class of antidepressant drugs that
offer improved efficacy and/or faster onset of action relative to
SSRIs.6 Duloxetine has also been shown be effective in other ther-
apeutic indications including neuropathic pain5a,7 and stress uri-
nary incontinence.8 Accordingly, considerable research efforts
continue to focus on the development of pharmaceutical agents
that possess norepinephrine reuptake inhibition either selec-
tively9,10 or in combination with serotonin reuptake inhibition
(Fig. 1).11
Fluoxetine (1), atomoxetine (2), reboxetine (3), and duloxetine
(5) all share a common aryloxypropanamine scaffold (Fig. 2). The
application of this structural framework has generated a number
of potent monoamine reuptake inhibitors. In our continued inter-
est to identify novel NRIs9 to probe their therapeutic potential,
we designed a new series of 3-(arylamino)-3-phenylpropan-2-
olamines based on the well-known aryloxypropanamine scaffold
(Fig. 2), where the aryloxy domain is replaced by an arylamino
moiety, and a hydroxyl group is incorporated into the amino
side chain to mimic the b-hydroxyl of NE.12 These compounds
were then tested for their ability to block the biogenic amine
* Corresponding author. Tel.: +1 484 865 8432; fax: +1 484 865 9399.
E-mail address: vua@wyeth.com (A.T. Vu).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.054

A. T. Vu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2464–2467
2465
er–Clarke methylation of 10d (R1 = 4-Me, R2 = H, R3 = Me) was
accomplished by heating with formaldehyde in formic acid to give
compound (R,S/S,R)-11. Analogue (R,R/S,S)-10v is an anti diastereo-
mer that was derived from the corresponding anti ester 8v (R = Et,
R1 and R2 = H).16 Finally, amines 10 and 11 were converted to
hydrochloride salts prior to biological evaluation.
F3C
O
N
H
O
N
H
O
NH
Me
O
O
Fluoxetine (1)
Atomoxetine (2)
Reboxetine (3)
Compounds 10 and 11 were evaluated in vitro for their ability
to inhibit both the uptake of norepinephrine in MDCK-Net6 cells
stably transfected with human norepinephrine transporter (hNET)
and serotonin in JAR cells stably transfected with the human sero-
tonin transporter (hSERT). Selected compounds were also evalu-
ated for their inhibition of [3H]WIN-35428 radioligand binding to
the human dopamine transporter (hDAT). Detailed experimental
protocols for these inhibitory assays were reported previously.9c
Results of the in vitro screening are presented in Table 1.17
The unsubstituted 3-(arylamino)-3-phenylpropan-2-olamine
10a displayed significant norepinephrine reuptake inhibition.
Incorporating a small R1 substituent such as methyl, 4-fluoro,
chloro or methoxy group (10b–k) onto the arylamino ring offered
essentially no improvement on the hNET potency relative to their
unsubstituted congener 10a. A few analogues 10d, 10g, and 10h
however showed comparable norepinephrine reuptake inhibition
to that of 10a. Methoxy substitution (10i–k) or substitution at
the ortho position of this ring (10b, 10f and 10i) caused a decrease
in the hNET potency compared to 10a. For phenyl ring substitution,
among several small R2 groups investigated (10m–p), the 3-fluoro
substituent (10m) provided an enhancement on the hNET potency
relative to 10a. Compound 10m was the most potent NRI (hNET
IC50 = 12 nM) among the target compounds presented. Examining
the effect of the pendant amino group substitution (10q–u) re-
vealed that this region of the molecule was rather sensitive to
modification, and that there was an intrinsic preference for sec-
ondary methylamines. For example, primary amines 10q, 10s,
and 10u showed weaker hNET potencies compared to their corre-
sponding secondary methylamines 10a, 10m, and 10p; whereas
slightly larger secondary ethylamines 10r and 10t, and dimethyl
tertiary amine 11 resulted in a poor norepinephrine inhibitory
activity. The anti diastereomer 10v was substantially less potent
at hNET than its syn diastereomer 10a.
N
S
OH
O
N
H
O
Venlafaxine (4)
Duloxetine (5)
Figure 1.
R2
R1
R3
O
N
H
N
N
OH R4
Aryloxypropanamine
Figure 2. Scaffold evolution.
transporters. Herein we describe the synthesis and structure–
activity relationship of the 3-(arylamino)-3-phenylpropan-2-ola-
mine series.
The synthesis of the 3-(arylamino)-3-phenylpropan-2-olamines
is illustrated in Scheme 1, which follows an existing route reported
by Melloni.13 All target compounds in Table 1 were prepared as
racemic, single diastereomers.14 The synthesis started from trans-
3-phenylglycidates 7 which were obtained either from commercial
sources (for R2 = H, 4-OMe), or were prepared by a two-step reac-
tion sequence shown in Scheme 1. Thus commercially available
trans-cinnamic acids (R2 = 3-F, 3-Cl, and 4-Cl) were converted to
trans-cinnamate esters 6 either by O-methylation of the carboxylic
acid group mediated by cesium carbonate, or by Fischer esterifica-
tion in ethanol. Subsequent epoxidation using methyl(trifluoro-
methyl)dioxirane,15 which was generated in situ from
trifluoroacetone and oxone, provided trans-3-phenylglycidates 7.
Thermally induced epoxide ring-opening of 7 with various N-
methylanilines afforded syn-esters 8 regioselectively and stereo-
specifically. Direct amidation of 8 by heating with excess amines
(ammonia, methylamine, and ethylamine), followed by borane
reduction furnished target compounds (R,S/S,R)-syn-10. Eschweil-
A number of 3-(arylamino)-3-phenylpropan-2-olamines also
displayed substantial serotonin reuptake inhibition. However cer-
tain substitution on the arylamino ring exerted considerable ef-
fects on the hSERT potency. For example, the 2-methyl (10b) and
2-methoxy (10i) groups caused a more significant decrease in the
inhibitory activity for serotonin than for norepinephrine, thus
resulting in overall selectivity of 7–12-fold of hNET over hSERT. A
similar effect was observed for compound 10l where the phenyla-
R1
R2
R2
R2
a
b
c
+
OH
OR
OR
NH
O
O
O
O
6, R = Me, Et
7
R2
R2
R2
H3C
O
O
e
d
f
R1
R1
R1
R3
R3
N
OR
N
N
H
N
N
N
N
10d
H
OH
OH
OH
OH
8
9
(R,S/S,R)-10
(R,S/S,R)-11
Scheme 1. Reagents and conditions: (a) MeI, Cs2CO3, acetone, 65 °C, 1.5 h, or EtOH, cat. H2SO4, 70 °C, 85–99%; (b) CF3COCH3, Na2ÁEDTA, then oxone/NaHCO3, CH3CN/H2O,
0 °C–rt, 12 h, 93–99%; (c) 135 °C, neat, 3 h, 75–97%; (d) For R3 = H: NH4OH, EtOH, 80 °C, sealed tube, 12 h, or 7 N NH3 in MeOH, 100 °C, sealed tube, 5 h, 31–54%; For R3 = Me:
33 wt % CH3NH2 in EtOH, 80 °C, sealed tube, 5 h, 80–99%; For R3 = Et:2M EtNH2 in MeOH, 120 °C, sealed tube, 48 h, 46–57%; (e) BH3ÁTHF, 70 °C, 1 h, 58–97%; (f) H2C = O,
HCO2H, H2O, 70 °C, 1 h, 86%.

2466
A. T. Vu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2464–2467
Table 1
Inhibitory activity of 3-(arylamino)-3-phenylpropan-2-olamines and reference compounds at hNET, hSERT and hDATa
R2
R1
R3
N
N
N
N
H
N
N
H
OH R4
OH
OH
(R,S/S,R)-syn-10a-k, 10m-u, 11
(R,S/S,R)-syn-10l
(R,R/S,S)-anti-10v
R1
R2
R3
R4
hNET IC50 (nM)
hSERT IC50 (nM)
hSERT IC50/hNET IC50
hDAT % inh.@ 1
l
Me
b
c
d
Compound
Fluoxetine (1)
Atomoxetine (2)
563
3
10
48
0.02
16
Reboxetine (3)
Duloxetine (5)
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
3
4
30
217
61
29
62
240
20
23
300
400
99
120
12
73
110
34
242
3
76
2607
32
73
33
286
41
22
2105
17
81
0.75
2.6
12
0.5
2.5
0.5
1.2
2.1
1
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
9
6
8
8
6
7
33
4
4
1
4
10
33
4
2-Me
3-Me
4-Me
4-F
2-Cl
3-Cl
4-Cl
2-OMe
3-OMe
4-OMe
7
0.04
0.03
7
9.3
3.3
1.5
1.6
2.9
10k
10l
3
836
112
237
167
55
10m
10n
10o
10p
10q
10r
11
10s
10t
H
H
H
H
3-F
Me
Me
Me
Me
H
Et
Me
H
H
H
H
H
H
H
Me
H
H
H
3-Cl
4-Cl
4-OMe
H
H
H
3-F
3-Cl
4-OMe
0
H
68
196
4-Me
4-Me
H
H
H
32%f
32%f
550
31%f
156
1100
439
0.8
Et
H
10u
183
416
1.2
0.4
10
10vg
a
All 3-(arylamino)-3-phenylpropan-2-olamines are racemic, single diastereomers. Compounds 10a–u and 11 are syn diastereomers with R,S/S,R stereochemistry.
Inhibition of norepinephrine uptake in MDCK-Net6 cells, stably transfected with human NET. Desipramine (IC50 = 3.4 1.6 nM) was used as a standard.
Inhibition of serotonin uptake in JAR cells, stably transfected with human SERT. Fluoxetine (IC50 = 10 3.1 nM) was used as a standard.
b
c
d
Unitless value as a ratio in which higher values represent greater NET selectivity, a value of 1 represents no selectivity, and values approaching 0 represent SERT
selectivity.
e
Inhibition of [3H]WIN-35,428 binding to membranes from CHO cells expressing recombinant hDAT. Mazindol (IC50 = 22 6.5 nM) was used as a standard.
f
Percent inhibition measured at a concentration of 1
lM.
g
Compound 10v is an anti diastereomer of 10a with R,R/S,S stereochemistry.
mino moiety was replaced by a 1-naphthylamino group. In con-
trast, the 3-methoxy (10j) and 4-methoxy (10k) groups signifi-
cantly increased the hSERT potencies while weakening the hNET
inhibition (vs 10a), thus engendering substantial selectivity for
hSERT. Compound 10k was the most potent serotonin reuptake
inhibitor (hSERT IC50 = 3 nM) among the target molecules reported.
Compound 10m bearing a 3-fluoro substituent on phenyl ring
exhibited a modest hNET selectivity of ninefold, which was due
to its enhanced hNET potency and slightly reduced hSERT potency
relative to 10a.
tory activity and selectivity will be reported in future
publications.
Acknowledgements
The authors thank the Wyeth Discovery Analytical Chemistry
department for the spectral data and compound analysis. Special
thanks to Dr. Ronald Magolda and Dr. Magid Abou-Gharbia for
their encouragement and support.
A number of compounds were further evaluated for their dopa-
mine transporter binding affinity and were found to be very weak
ligands for hDAT (633% inh. @ 1 lM).
References and notes
1. (a) Walter, M. W. Drug. Dev. Res. 2005, 65, 97–118; (b) Bymaster, F. P.;
McNamara, R. K.; Tran, P. V. Exp. Opin. Invest. Drugs 2003, 12, 531–543.
2. For a recent review on norepinephrine reuptake inhibitors, see: Babu, R. P. K.;
Maiti, S. N. Heterocycles 2006, 69, 539–567.
3. Christman, A. K.; Fermo, D. J.; Markowitz, J. S. Pharmacotherapy 2004, 24, 1020–
1026.
4. Hajos, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.; Brown, M. T.; Wong, E. H. F.
CNS Drug Rev. 2004, 10, 23–44.
5. (a) Krell, H. V.; Leuchter, A. F.; Cook, I. A.; Abrams, M. Psychosomatics 2005, 46,
379–384; (b) Berigan, T. Can. J. Psychiatry 2004, 49, 499–500.
6. Tran, P. V.; Bymaster, F. P.; McNamara, R. K.; Potter, W. Z. J. Clin.
Psychopharmacol. 2003, 23, 78–86.
In summary, we have designed and investigated a new series
of 3-(arylamino)-3-phenylpropan-2-olamines. A number of ana-
logues were found to be potent SNRIs. The compounds in this
class displayed a wide range selectivity for either hNET or hSERT
depending on the substituents on both the arylamino and phenyl
rings. Moreover, the weak dopamine binding affinity of this ser-
ies indicated good selectivity over the dopamine transporter.
Additionally, most 3-(arylamino)-3-phenylpropan-2-olamines
including 10m and 10k have low TPSA (35–44 Å2), and are
therefore anticipated to cross the blood-brain barrier.18 Further
exploration of this scaffold to maximize norepinephrine inhibi-
7. Collins, S. D.; Chessell, I. P. Exp. Opin. Emerg. Drugs 2005, 10, 95–108.
8. McCormack, P. L.; Keating, G. M. Drugs 2004, 64, 2567–2573.
9. (a) Zhang, P.; Terefenko, E. A.; McComas, C. C.; Mahaney, P.; Vu, A.; Trybulski,
E.; Koury, E.; Johnston, G.; Bray, J.; Deecher, D. Bioorg. Med. Chem. Lett. 2008, 18,

A. T. Vu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2464–2467
2467
6067–6070; (b) McComas, C. C.; Vu, A. T.; Mahaney, P. E.; Cohn, S. T.; Fensome,
A.; Marella, M. A.; Nogel, L.; Trybulski, E. J.; Ye, F.; Zhang, P.; Alfinito, P.; Bray, J.
A.; Johnston, G. H.; Koury, E. J.; Deecher, D. C. Bioorg. Med. Chem. Lett. 2008, 18,
4929–4931; (c) Mahaney, P. E.; Gavrin, L. K.; Trybulski, E. J.; Stack, G. P.; Vu, A.
T.; Cohn, S. T.; Ye, F.; Belardi, J. K.; Santilli, A. A.; Sabatucci, J. P.; Leiter, J.;
Johnston, G. H.; Bray, J. A.; Burroughs, K. D.; Cosmi, S. A.; Leventhal, L.; Koury, E.
J.; Zhang, Y.; Mugford, C. A.; Ho, D. M.; Rosenzweig-Lipson, S. J.; Platt, B.; Smith,
V. A.; Deecher, D. C. J. Med. Chem. 2008, 51, 4038–4049; (d) Mahaney, P. E.; Vu,
A. T.; McComas, C. C.; Zhang, P.; Nogle, L. M.; Watts, W. L.; Sarkahian, A.;
Leventhal, L.; Sullivan, N. R.; Uveges, A. J.; Trybulski, E. J. Bioorg. Med. Chem.
2006, 14, 8455–8466.
Greene, K.; Hoople, D.; Mackenny, M.; Para, K. S.; Reeves, K.; Ryckmans,
T.; Stiff, C.; Stobie, A.; Wakenhut, F.; Whitlock, G. A. Bioorg. Med. Chem.
Lett. 2008, 18, 2562–2566; (d) Whitlock, G. A.; Blagg, J.; Fish, P. V.
Bioorg. Med. Chem. Lett. 2008, 18, 596–599.
12. Introduction of a b-hydroxyl group into the aryloxypropanamine framework
was described previously by Melloni and co-workers. See Ref. 13.
13. Melloni, P.; Carniel, G.; Torre, A. D.; Bonsignori, A.; Buonamici, M.; Pozzi, O.;
Ricciardi, S.; Rossi, A. C. Eur. J. Med. Chem. 1984, 19, 235–242.
14. For detailed synthetic procedures, see: US 2008085938 A1.
15. Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887–3889.
16. The epoxide ring-opening reaction of trans-ethyl 3-phenylglycidate
(commercially available from Aldrich, which also contains a minor amount
of the cis epoxide) by N-methylaniline gave syn ester 8a as a major product and
anti ester 8v as a minor product. The structure determination and relative
stereochemistry assignment of 8a and 8v were supported by one-dimensional
proton NMR spectra as well as by two-dimensional NMR experiments
including 1H–1H gCOSY (gradient Correlation Spectroscopy) and NOESY,
1H–13C gHSQC, gHMBC and 1,1-ADEQUATE.
10. (a) Xu, W.; Gray, D. L.; Glase, S. A.; Barta, N. S. Bioorg. Med. Chem. Lett. 2008, 18,
5550–5553; (b) Hudson, S.; Kiankarimi, M.; Eccles, W.; Mostofi, Y. S.; Genicot,
M. J.; Dwight, W.; Fleck, B. A.; Gogas, K.; Wade, W. S. Bioorg. Med. Chem. Lett.
2008, 18, 4495–4498; (c) Hudson, S.; Kiankarimi, M.; Eccles, W.; Dwight, W.;
Mostofi, Y. S.; Genicot, M. J.; Fleck, B. A.; Gogas, K.; Aparicio, A.; Wang, H.; Wen,
J.; Wade, W. S. Bioorg. Med. Chem. Lett. 2008, 18, 4491–4494; (d) Wu, D.;
Pontillo, J.; Ching, B.; Hudson, S.; Gao, Y.; Fleck, B. A.; Gogas, K.; Wade, W. S.
Bioorg. Med. Chem. Lett. 2008, 18, 4224–4227; (e) Cases-Thomas, M. J.; Masters,
J. J.; Walter, M. W.; Campbell, G.; Haughton, L.; Gallagher, P. T.; Dobson, D. R.;
Mancuso, V.; Bonnier, B.; Giard, T.; Defrance, T.; Vanmarsenille, M.; Ledgard, A.;
White, C.; Ouwerkerk-Mahadevan, S.; Brunelle, F. J.; Dezutter, N. A.; Herbots, C.
A.; Lienard, J. Y.; Findlay, J.; Hayhurst, L.; Boot, J.; Thompson, L. K.; Hemrick-
Luecke, S. Bioorg. Med. Chem. Lett. 2006, 16, 2022–2025; (f) Beadle, C. D.; Boot,
J.; Camp, N. P.; Dezutter, N.; Findlay, J.; Hayhurst, L.; Masters, J. J.; Penariol, R.;
Walter, M. W. Bioorg. Med. Chem. Lett. 2005, 15, 4432–4437.
O
O
N
O
N
O
OH
OH
8a
8v
11. (a) Wakenhut, F.; Fish, P. V.; Fray, M. J.; Gurrell, I.; Mills, J. E.; Stobie,
A.; Whitlock, G. A. Bioorg. Med. Chem. Lett. 2008, 18, 4308–4311; (b)
Whitlock, G. A.; Fish, P. V.; Fray, M. J.; Stobie, A.; Wakenhut, F. Bioorg.
Med. Chem. Lett. 2008, 18, 2896–2899; (c) Fish, P. V.; Deur, C.; Gan, X.;
17. Since the in vitro data in Table 1 are for racemic compounds, it is possible
that the contributing effects from each enantiomer may be unequal. See Ref.
11c.
18. Hitchcock, S. A.; Pennington, L. D. J. Med. Chem. 2006, 49, 7559–7583.