Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake.

Article abstract of DOI:10.1016/j.bmcl.2003.08.079

A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta) has proven to be effective in clinical trials for the treatment of depression.

Full text of DOI:10.1016/j.bmcl.2003.08.079

Bioorganic & Medicinal Chemistry Letters 13 (2003) 4477–4480
Duloxetine (CymbaltaTM), a Dual Inhibitor of Serotonin and
Norepinephrine Reuptake
F. P. Bymaster,a E. E. Beedle,a J. Findlay,b P. T. Gallagher,b,* J. H. Krushinski,a
S. Mitchell,b D. W. Robertson,a D. C. Thompson,a L. Wallaceb and D. T. Wonga
aLilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
bEli Lilly and Company, Ltd, Lilly Research Centre, Windlesham, Surrey GU20 6PH, UK
Received 12 June 2003; revised 29 August 2003; accepted 29 August 2003
Abstract—A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both sero-
tonin and norepinephrine reuptake. One member of this series, duloxetine (CymbaltaTM) has proven to be effective in clinical trials
for the treatment of depression.
# 2003 Elsevier Ltd. All rights reserved.
Major depressive disorder is currently the fourth leading
cause of disease or disability worldwide and is projected
to rise to second by 2020.1 Unfortunately current mono-
therapy for depression for example, Selective Serotonin
Reuptake Inhibitors (SSRI’s) provide remission in only
approximately one-third of cases in controlled trials.2
That enhancing both serotonergic and noradrenergic
neurotransmission results in antidepressant efficacy is
now supported by clinical experience with duloxetine
(CymbaltaTM).3
the amino-ether chain resulted in an improvement in
both the 5-HT and the NE uptake affinity.
The synthesis of 7 started with the reduction of 3-dime-
thylamino-1-phenylpropan-1-one with sodium borohy-
dride in ethanol to give 3-dimethylamino-1-
phenylpropan-1-ol.5 The aminopropanol was then aryl-
ated with 1-fluoronaphthalene, the resultant amino
ether was then mono-demethylated in a two step pro-
cess. Treatment with trichloroethylchloroformate and
conversion of the resultant carbamate with zinc metal
Herein we report the activity of a series of naphthal-
enyloxy-arylpropylamines one of which, duloxetine (25)
demonstrates high affinity for the serotonin (5-HT) and
norepinephrine (NE) transporters and has proven effective
in clinical trials for the treatment of depression.3
Table 1. Binding affinities at the norepinephrine and serotonin
transporters for the 1- and 2-linked naphthyl ethers compounds 1–64
The synthesis of naphthyl ethers 1–6 (Table 1) started
from either 1- or 2-naphthol (Scheme 1) followed by
alkylation with the appropriate di-halo alkane. The
resultant haloalkyl ethers were converted to the
methylamino ethers with methylamine in either DMF,
THF or methanol in the presence of sodium iodide.
Compd
Naphthyl
n
5-HT
NE
1
2
3
4
5
6
1
1
1
1
2
2
1
2
3
4
2
3
2%a
75b
31b
35.5%a
23%a
32%a
17%c
25%c
25.5%c
23%c
39%c
17%c
Variations in chain length and naphthalene substitution
position did not produce the desired levels of NE uptake
activity, however incorporation of a phenyl ring (7) into
a% Inhibition @ 0.1 mM.
bKi, nM.
c% Inhibition @ 1 mM. Binding affinities and displacement measure-
ments were done in triplicate.
*Corresponding author. Tel.: +44-(0)1276-483536; fax: +44-(0)1276-
483525; e-mail: gallagher_p@lilly.com
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.08.079

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F. P. Bymaster et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4477–4480
Table 2. Binding affinities at the norepinephrine and serotonin
transporters for the substituted phenyl naphthyl ethers 7–20
Scheme 1. Synthesis of naphthyl ethers 1–6. Reagents and conditions:
(a) NaH, DMF, and for n=1 Br(CH2)2Br; for n=2 Br(CH2)3Br; for
n=3 Br(CH2)4Br; for n=4 Br(CH2)5Cl; (b) for n=1 & 2, MeNH2,
THF; for n=3 MeNH2, MeOH; for n=4 MeNH2, DMF, NaI; (c)
NaH, DMF, for n=2 Br(CH2)2Br; for n=3 Br(CH2)4Cl; (d) for n=2,
MeNH2, THF; for n=3 MeNH2, DMF, NaI.
Compd
R
5-HTa
NE
7
8
9
H
4-F
3-Br
4-Br
2.4
0.95
7.6
4.1
10
20a
42a
67a
10
11
12
13
14
15
16
17
18
19
20
160a
38%b
70a
2-CF3
3-CF3
4-CF3
4-Cl
2-Me
3-Me
4-Me
2-MeO
3-MeO
4-MeO
19
14.5
3.8
2.0
4.0
2.1
2.3
2.2
3.5
55%b
78a
110a
40a
36a
56%b
81a
Scheme 2. (a) NaBH4, EtOH; (b) 1-fluoronaphthalene, NaH, DMA;
(c) Cl3CCH2OCOCl, benzene; (d) HCOOH, Zn, DMF.
74a
aKi, nM.
b% Inhibition @ 1 mM. Binding affinities and displacement measure-
ments were done in triplicate.
and formic acid in DMF provided the mono-
methylamine 7 (Scheme 2).
Table 3. Binding affinities at the norepinephrine and serotonin
transporters for the heterocyclic naphthyl ethers 21–24
Compounds 8–20 in Table 2 were synthesized by the
method used for compound 7. Substitution of the phenyl
ring was next attempted but both the introduction of
electron donating, electron withdrawing or neutral sub-
stituents in either the 2-, 3- or 4-positions of the phenyl
ring was not rewarded with improvement of affinity at
the NE transporter.
Compd
R
5-HTa
NEa
A notable feature is the improvement in 5-HT uptake
affinity on introducing a 4-fluoro susbtituent to the
phenyl ring (8). As substitution of the phenyl ring did
not improve the inhibition of NE uptake while main-
taining inhibition of 5-HT uptake, isosteric replacement
of the phenyl ring was attempted. Thus, heterocyclic
alternatives to the phenyl ring of compound 7 were
synthesized (Table 3).
7
Phenyl
2.4
1.4
1.1
0.7
6.4
20
20
21
20
55
21
22
23
24
Thien-2-yl
Thien-3-yl
Furan-2-yl
Thiazol-2-yl
aKi, nM. Binding affinities were done in triplicate.
Compounds 21–23 were synthesized analogously to the
thiazole analogue (24). Thus 2-acetylthiazole was reacted
with dimethylamine hydrochloride and paraformalde-
hyde under Mannich conditions to give 3-dimethyla-
mino-1-thiazol-2-yl-propan-1-one (Scheme 3). The
aminopropanone was reduced with sodium borohydride
in methanol and the resultant alcohol was coupled to 1-
fluoronaphthalene with sodium hydride in dimethylace-
tamide. Finally dealkylation of the tertiary amine was
achieved in two steps, an intermediate phenyl carbamate
was formed with phenylchlorofomate and the carbamate
then hydrolyzed with sodium hydroxide in propylene
glycol to give methyl-[3-(naphthalen-1-yloxy)-3-thiazol-
2-yl-propyl]-amine (24).
Compound 21 was then chosen for further study. Two
chiral routes to the enantiomers of 21 were developed.6
Both routes (Scheme 4) started from a common inter-
mediate 2-(3-chloropropionyl)thiophene and are depic-
ted for enantiomer 25.7 Route A commenced with an
enantioselective reduction using R-1-methyl-3,3-diphe-
nyl-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole in the
presence of borane in THF.
The resultant chloroalcohol was then transformed via
the iodide to S-3-methylamino-1-thiophen-2-yl-propan-
1-ol. This was then used in a nucleophilic displacement
reaction with 1-fluoronaphthalene to give 25. Route B
utilized S-1-methyl-3,3-diphenyl-tetrahydropyrrolo[1,2-
c][1,3,2]oxazaborole to produce R-3-chloro-1-thiophen-
2-yl-propan-1-ol. This was then subjected to a Mitsu-
nobu reaction with 1-naphthol, diethylazodicarboxylate
and triphenylphosphine and the resultant chloroether
Of the heterocyclic alternatives synthesized, the thienyl
and furan-2-yl analogues 21–23 demonstrated improved
5-HT uptake inhibition, with the furan analogue (23)
having a Ki value of 0.7 nM.

F. P. Bymaster et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4477–4480
4479
Figure 1.
Scheme 3. (a) Paraformaldehyde, (CH3)2NH–HCl, 12N HCl, EtOH;
(b) K2CO3, H2O, NaBH4, MeOH; (c) 1-fluoronaphthalene, NaH,
DMA; (d) PhOCOCl, toluene; (e) NaOH, propylene glycol.
From Table 4 it can also be seen that by comparison to
the SSRI fluoxetine (27) and the selective NE reuptake
inhibitor atomoxetine (28) (Fig. 1), that 25 is a potent
dual inhibitor of 5-HT and NE.
Further in vivo evaluation of 25 was also made, thus in
microdialysis experiments to determine the increase in
synaptic concentration of NE and 5-HT in rat, follow-
ing administration of 25, at 10 mg/kg po increases in
basal levels of NE and 5-HT by 208Æ31% and
353Æ62%, respectively, were found. Full microdialysis
results will be published elsewhere.
Scheme 4. Synthesis of 25. Reagents and conditions: Route A (a) R-1-
methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole, BH3,
THF: (b) NaI, acetone; (c) methylamine, THF; (d) 1-fluoro-
naphthalene, NaH, DMA; Route B (e) S-1-methyl-3,3-diphenyl-tetra-
hydro-pyrrolo[1,2-c][1,3,2]oxazaborole, BH3, THF: (f) 1-naphthol,
DEAD, Ph3P.
In summary 25 inhibits binding to human cell lines
expressing NE and 5-HT transporters, inhibits the re-
uptake of NE and 5-HT in rat synaptosomes of 5-HT
and NE and increases NE and 5-HT in rat pre-frontal
cortex. Compound 25 has been progressed to the clinic
(as duloxetine hydrochloride, CymbaltaTM) and has been
shown to be effective in the treatment of depression.3
Table 4. Inhibition of norepinephrine and serotonin uptake into rat
synaptosomes for the enantiomers of compound 2110
Acknowledgements
The authors would like to thank Dr. John Schaus for
helpful advice in compiling this manuscript.
Compd
Compd
5-HTa
NEa
DAa
25
26
27
28
S-21
R-21
Fluoxetine
Atomoxetine
4.6
8.8
48
1500
16
16
2000
4
370
660
6000
2000
References and Notes
aKi, nM.
was converted to S-methyl-[3-(naphthalen-1-yloxy)-3-
thiophen-2-yl-propyl]-amine 25 with methylamine in
THF.6,8,9
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Compounds 25 and 26 were then assessed for their
ability to inhibit synaptosomal uptake into rat synapto-
somes (Table 4).10 Inhibition of monoamine uptake into
rat synaptosomes has been used to assess the functional
ability of a compound to block re-uptake of mono-
amines. The resolved enantiomers 25 and 26 proved to
be equipotent at the NE transporters, however com-
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The method for determining the Ki is the same for each trans-
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0.8, 7.5 and 240 at the 5-HT, NE and dopamine uptake
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[3H]-Nisoxetine binding assay: Each well of a 96-well micro-
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50 mL 2nM-[N-methyl-3H]-Nisoxetine hydrochloride (70–87
Ci/mmol) (NEN)
75 mL Assay buffer (50mM Tris HCl pH 7.4 containing 300
mM NaCl and 5 mM KCl)
.

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F. P. Bymaster et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4477–4480
25 mL Test compound, assay buffer (total binding) or 10 mM
Desipramine HCl (non-specific binding)
6. Wheeler, W. J.; Kuo, F. J. Labelled Compd. Radiopharm.
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50 mL WGA PVT SPA Beads (10 mg/mL)
50 mL Membrane (0.2 mg protein per mL)
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T. Phosphorus and Sulfur and the Related Elements 1987, 33,
25.
The microtitre plates were incubated at room temperature for
10 h prior to reading in a Trilux scintillation counter. The
results were analyzed using an automatic spline fitting
programme (Multicalc, Packard, Milton Keynes, UK) to pro-
vide Ki values for each of the test compounds.
5. Glennon, R. A.; Jacyno, J. M.; Salley, J. J. J. Med. Chem.
1982, 25, 68.
8. For 259 [a]D (c=1, MeOH)=+117ꢀ.
9. Deeter, J.; Frazier, J.; Staten, G.; Staszak, M.; Weigel, L.
Tetrahedron Lett. 1990, 31, 7101.
10. Wong, D. T.; Bymaster, F. P.; Mayle, D. A.; Reid, L. R.;
Krushinski, J. H.; Robertson, D. W. Neuropsychopharmacol-
ogy 1993, 8, 23.