First dual NK1 antagonists-serotonin reuptake inhibitors: Synthesis and SAR of a new class of potential antidepressants

Article abstract of DOI:10.1016/S0960-894X(01)00727-2

Compounds combining NK₁ antagonism and serotonin reuptake inhibition are described, and potentially represent a new generation of antidepressants. Compound 24 displays good affinities for both the NK₁ receptor and the serotonin reuptake site (32 and 25 nM, respectively).

Full text of DOI:10.1016/S0960-894X(01)00727-2

Bioorganic & Medicinal Chemistry Letters 12 (2002) 261–264
First Dual NK1 Antagonists–Serotonin Reuptake Inhibitors:
Synthesis and SAR of a New Class of Potential Antidepressants
Thomas Ryckmans,a,* Laurent Balancon,a Olivier Berton,b Christophe Genicot,a
Yves Lamberty,b Benedicte Lallemand,a Patrick Pasau,a Nathalie Pirlot,a
Luc Querea and Patrice Talagaa
aChemical Research, R&D, UCB Pharma SA, Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium
bPreclinical CNS Research, R&D, UCB Pharma SA, Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium
Received 21 September 2001; revised 26 October 2001; accepted 30 October 2001
Abstract—Compounds combining NK1 antagonism and serotonin reuptake inhibition are described, and potentially represent a
new generation of antidepressants. Compound 24 displays good affinities for both the NK1 receptor and the serotonin reuptake site
(32 and 25 nM, respectively). # 2002 Elsevier Science Ltd. All rights reserved.
Depression is reported to affect up to 10% of the
population, with a lifetime prevalence of 19%1 and is
linked with a significant mortality.
More recently, third generation antidepressants have
appeared, such as noradrenaline reuptake inhibitors
(NRI), serotonin–noradrenaline reuptake inhibitors
(SNRI) and noradrenaline–dopamine reuptake inhibi-
tors (NDRI). The recently introduced Mirtazapine (3) is
First-generation tricyclic antidepressants such as Imi-
pramine (1) induce severe side effects (e.g., anti-
cholinergic).2 They were replaced in the 1980’s by the
selective serotonin reuptake inhibitors (SSRI) such as
Paroxetine (2) (Scheme 1).
a
noradrenergic and specific serotoninergic anti-
depressant (NaSSa) displaying affinities for the a2,
5-HT2, 5-HT3 and H1 receptors. Compared with SSRIs,
Mirtazapine is reported to have a slightly faster onset of
action, a beneficial effect on sleep quality, and fewer
side-effects such as anxiety3 and sexual dysfunction.4
However, a common problem in current antidepressant
therapies is their slow onset of action, since a delay of
about 4 weeks is normally observed between the begin-
ning of the treatment and alleviation of the symptoms.
This delay appears to parallel the progressive desensiti-
zation of somatodendritic 5HT1A receptors, increasing
serotoninergic function, thus allowing alleviation of
depressive symptoms. Indeed, clinical evidence shows
that co-administration of a 5-HT1A antagonist such as
Pindolol has a beneficial effect on the onset of action of
SSRIs.5,6 Moreover, this combination has allowed
major improvements for SSRI-resistant patients. Sero-
tonin reuptake inhibitors with an added 5-HT1A antag-
onism component are thus actively researched.7,8
Scheme 1. Examples of first, second and third generation anti-
depressants.
SSRIs have fewer side effects than tricyclics, but never-
theless display their own side effects, such as gastro-
intestinal distress, anxiety, insomnia and sexual
dysfunction due to their indirect activation (through
elevation of 5-HT levels) of all 5-HT receptors.
Several lines of research6,9 are being pursued for the
discovery of new antidepressants with less side effects, a
faster onset of action and a better rate of response,
including non-monoaminergic approaches such as
*Corresponding author. Tel.:+32-2-386-2699; fax:+32-2-386-2704;
e-mail: thomas.ryckmans@ucb-group.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00727-2

262
T. Ryckmans et al. / Bioorg. Med. Chem. Lett. 12 (2002) 261–264
CRF10ꢀ14 and NK1 antagonists.15ꢀ18 In mice, the
genetic disruption of NK1 receptor decreases anxiety-
related behavior;19 moreover NK1 antagonists have
been reported to have a faster onset of action than Imi-
pramine (1) in an animal model of depression.20
dihydrocinnamic acid derivative using HOBT/DCC28
gave the intermediate amides 7, which were deprotected
with TFA to allow the isolation of compounds 8–11.
Compounds 12 and 13 were obtained by Borane reduc-
tion of amides 7 (with R1=4-fluorophenyl and 4-fluoro-
benzyl) in THF followed by deprotection with TFA.
Finally, robust efficacy in treating depression was
reported in clinical trials for two NK1 antagonists, MK-
86916 (4) and CP 122,72122,21 (5) (Scheme 2).
Protected amines 6 react with chloroacetyl chloride in
CH2Cl2 in the presence of solid K2CO3 to afford the
intermediate chloroacetamides 14.29 Addition of phe-
nols to derivatives 14 in acetonitrile in the presence of
Cs2CO3 followed by TFA deprotection allows the iso-
lation of compounds 15–29 (Scheme 4).30
Scheme 2. MK-869 and CP 122,721.
Scheme 4. (e) Chloroacetyl chloride, K2CO3, CH2Cl2; (f) phenol,
Cs2CO3, CH3CN; (g) TFA, CH2Cl2.
NK1 antagonists are now believed to indirectly mod-
ulate 5-HT function, via Noradrenergic pathways19,23
and have been shown to attenuate presynaptic 5HT1A
receptor function.7,19
Amides 9–11 had a better affinity than 8 for the NK1
receptor while affinity for the ST remained unchanged.
Reduction of the amide 8 to the amine 12 allowed a
significant increase in binding profile on both targets.
Reduction of amide 9 to 13 allowed an increase in affi-
nity for the ST but lowered the affinity for the NK1
receptor (Table 1).
Thus, combination of serotonin reuptake inhibition
with NK1 antagonism (modulating 5HT1A function)
may lead to a new class of antidepressants with an
improved onset of action and a better efficacy.
We now report the discovery of a family of potential
antidepressants that combine serotonin reuptake inhi-
bition and NK1 antagonism.
Table 1. Affinities26 of compounds 8–13 for the NK1 receptor and
the serotonin transporter (ST), and their lipophilicity
pIC50 STa
log k0IAM
a
Compd
R1
pIC50 NK1
Results
8
9
10
11
12
13
4-Fluorophenyl
4-Fluorobenzyl
3-Methylbenzyl
2-Chlorobenzyl
4-Fluorophenyl
4-Fluorobenzyl
6.7
7.5
7.6
7.0
7.3
6.9
6.6
6.5
6.7
6.7
7.4
7.6
2.9
2.9
3.2
3.2
3.9
3.8
Screening of the UCB compound collection on both the
NK1 receptor and the serotonin transporter (ST)
according to published procedures24ꢀ26 allowed the dis-
covery of compound 8. This compound displays modest
affinities for both the NK1 receptor and the ST and was
used as a starting point for this study. The preparation
of analogous compounds 9–13 and 15–29 starts with the
reductive amination of N-BOC protected piperidone with
aromatic amines,27 yielding the intermediate aminopi-
peridines 6 (Scheme 3). Coupling of amines 6 with a
aValues are means of two experiments.
The immobilized artificial membrane (IAM) stationary
phase method was chosen for mimicking the properties
of the passage over a cell membrane. At physiological
pH, the measured31 value of membrane affinity for amide
derivatives (8–11) predicts excellent drug absorption
properties32 if no major efflux mechanisms are involved.
In contrast the reduced compounds 12–103 are character-
ized by an enhanced lipophilicity (log k IAM of 3.9 and
3.8, respectively), thus lowering their potential as orally
active CNS agents.33 Moreover, such high values are often
linked with poor solubility and increased metabolism.
The exploration of the structure–affinity relationship of
this family of compounds was hampered by the scarcity of
commercially available dihydrocinnamic acids. We there-
fore modified the scaffold to a central, more hydrophilic
glycolyl part, and diversity was introduced from a com-
bination of readily available anilines, benzylamines
(seven R1 derivatives) and phenols (five R2 derivatives).
Scheme 3. (a) Amine, NaBH(OAc)3, dichloroethane, AcOH; (b) acid,
HOBT, DCC, DIPEA, THF–CH3CN; (c) BH3–THF, THF; (d) TFA,
CH2Cl2.

T. Ryckmans et al. / Bioorg. Med. Chem. Lett. 12 (2002) 261–264
263
Scanning the R1 moiety with a fixed 3,5-bis-tri-
fluoromethyl phenyl (15–21) showed that both phenyl
and benzyl moieties were allowed, with the exception of
the 3,5-dichloro derivative 20 which displayed low affi-
nity for the NK1 receptor (Table 2).
Delaunoy for skillful synthetic assistance, Reiner Die-
den and Alain Fauconnier for analytical assistance,
Liliane Ellens for skillful k0IAM measurements, Bruno
Fuks, Michel Gillard for setting up the binding assays,
Bernard Christophe and Marie-Rose Maleux for per-
forming isolated organs experiments and Sabrina Tem-
pesta and Eric Gillent for performing microdialysis
experiments.
Table 2. Affinities26 of compounds 15–29 for the NK1 receptor and
the serotonin transporter (ST), and their lipophilicity
Compd
R1
R2
pIC50
NK1
pIC50
STa
log
k0IAM
a
References and Notes
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
4-Fluorophenyl
3-Methylbenzyl
2-Chlorobenzyl
3-Chlorophenyl
3,4-Dichlorophenyl 3,5 di CF3
3,5-Dichlorophenyl 3,5 di CF3
3-Chlorobenzyl
3,4-Dichlorophenyl 3-F, 5-CF3
3,4-Dichlorophenyl 3,5 di Cl
3,4-Dichlorophenyl 3,5 di Me
3,4-Dichlorophenyl
3-Chlorobenzyl
3-Chlorobenzyl
3-Chlorobenzyl
3-Chlorobenzyl
3,5 di CF3
3,5 di CF3
3,5 di CF3
3,5 di CF3
6.5
7.1
6.9
6.7
6.2
6.6
6.8
6.8
6.8
6.8
6.8
7.4
7.5
7.5
7.6
7.0
7.3
7.6
7.7
2.5
3.3
3.2
3.0
3.4
3.4
3.4
3.0
3.2
2.7
2.5
2.9
3.1
2.6
2.4
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7.5
<5b
7.6
3,5 di CF3
<5b
7.0
7.6
5.9
<5b
6.9
7.0
<5b
3,5 di F
3-F, 5-CF3
3,5 di Cl
3,5 di Me
3,5 di F
aValues are means of two experiments.
bLess than 50% inhibition at 10ꢀ5 M.
Optimization of R2 using the most promising R1 sub-
stituents (3,4-dichlorophenyl and 3-chlorobenzyl) was
then started, using a series of 3,5-disubstituted phenols
(Table 2). Interestingly, introduction of smaller sub-
stituants in the 3,5 positions consistently increased the
affinity for the ST. Unsymmetrical R2 substituents such as
3-fluoro 5-trifluoromethyl were not tolerated and induced
12. McCarthy, J. R.; Heinrichs, S. C.; Grigoriadis, D. Ann.
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a loss of affinity for the N K receptor. An optimal overall
1
profile in terms of affinities and physicochemical properties
(k0IAM) was obtained with 3,5-dimethylphenyl (24, 28) and
3,5-dichloro phenyl (23) substituents.
In vitro, compound 24 behaved as a NK1 antagonist
inhibiting substance P-induced contraction of the iso-
lated guinea pig ileum34 (pA2 value of 6.88). To assess
central 5-HT reuptake blockade properties of 24, we
tested its ability to increase extracellular 5-HT in the
frontal cortex of freely moving rats by using intra-
cerebral microdialysis.35 Intraperitoneal administration
of the compound (3.2ꢁ10ꢀ5 mol/kg, n=2) increased
5-HT levels up to 350% of baseline. The peak effect
raised 1 h after the injection but was very transient since
5-HT levels returned to baseline after only 2 h, thus
suggesting a rapid metabolism of the compound.
16. Kramer, M. S.; Cutler, N.; Feighner, J.; Shrivastava, R.;
Carman, J.; Sramek, J. J.; Reines, S. A.; Liu, G.; Snavely, D.;
Wyatt-Knowles, E.; Hale, J. J.; Mills, S. G.; MaCcoss, M.;
Swain, C. J.; Harrison, T.; Hill, R. G.; Hefti, F.; Scolnick,
E. M.; Cascieri, M. A.; Chicchi, G. G.; Sadowski, S.; Wil-
liams, A. R.; Hewson, L.; Smith, D.; Rupniak, N. M. Science
1998, 281, 1640.
17. Kramer, M. S. Neuropeptides 2000, 34, 255.
18. Maubach, K. A.; Rupniak, N. M.; Kramer, M. S.; Hill,
R. G. Curr. Opin. Chem. Biol. 1999, 3, 481.
19. Santarelli, L.; Gobbi, G.; Debs, P. C.; Sibille, E. T.; Blier,
P.; Hen, R.; Heath, M. J. Proc. Natl. Acad. Sci. U.S.A. 2001,
98, 1912.
20. Papp, M.; Vassout, A.; Gentsch, C. Behav. Brain Res.
2000, 115, 19.
21. Rosen, T. J.; Coffman, K. J.; McLean, S.; Crawford, R. T.;
Bryce, D. K.; Gohda, Y.; Tsuchiya, M.; Nagahisa, A.; Nakane,
M.; Lowe, J. A. Bioorg. Med. Chem. Lett. 1998, 8, 281.
22. CNS DrugNews , December, 2000, 24.
23. Haddjeri, N.; Blier, P. NeuroReport 2000, 11, 1323.
24. Marcusson, J. O.; Bergstrom, M.; Eriksson, K.; Ross, S. B.
J. Neurochem. 1988, 50, 1783.
25. Aharony, D.; Catanese, C. A.; Woodhouse, D. P. J.
Pharmacol. Exp. Ther. 1991, 259, 146.
Thus, to the best of our knowledge, for the first time
dual NK1 antagonists and serotonin reuptake inhibiting
compounds are described. Such dual compounds offer a
potential as a new generation of antidepressants. Fur-
ther developments will be reported in due course.
Acknowledgements
The authors wish to thank Marie-Agnes Lassoie and
Valerie Verbois for the preparation of 8, Christel
26. The affinity of the test compounds for the ST was eval-
uated by a [3H]paroxetine binding assay. This binding was

264
T. Ryckmans et al. / Bioorg. Med. Chem. Lett. 12 (2002) 261–264
performed as described by Marcusson et al.24 with slight
modifications. 100–200 mg of membrane proteins from rat
cerebral cortex were incubated for 120 min at 25 ꢂC in 2 mL of
a 50 mM Tris–HCl (pH 7.4) buffer containing 2 mM MgCl2
and 0.05 nM radioligand. Non specific binding defined as the
residual binding was measured in the presence of 5 mM imi-
pramine.
mixture was stirred for 15 min. A solution of 1.26 g (3 mmol)
of the 14 derivative (R1=3,4-dichloro-phenyl) in 10 mL of
Acetonitrile was added and the reaction was stirred for 7 h.
The solvent was removed under reduced pressure, the residue
was partitioned between 30 mL of 0.1 NNaOH and ethyl
acetate. The aqueous phase was decanted and extracted twice
with 30 mL of ethyl acetate. Combined organic phases were
washed with brine, dried over magnesium sulfate and con-
centrated under reduced pressure. The resulting solid was
purified by flash chromatography on silica gel using CH2Cl2–
EtOH–aqueous ammonia (98–1.8–0.2%, v/v/v) as eluant. The
product was obtained as a solid, 0.98 g, yield 64.4%.
The affinity of the test compounds for the human NK1
receptor was measured as described by Aharony et al.25
Briefly, 10–20 mg of membrane proteins from CHO cells
expressing the human NK1 receptor were incubated for 60 min
ꢂ
at 25 C in 0.5 mL of the same buffer as above, supplemented
with 100 mg/mL bacitracine and 0.25 nM [3H] substance P.
The nonspecific binding was measured in the presence of 1 mM
CP-96345.
The compound was dissolved in 5 mL of CH2Cl2 and the
solution was cooled to 0 ꢂC. 6 mL of TFA were added and the
solution was stirred for 3 h. The solvent was removed under
reduced pressure, the residue was partitioned between aqueous
sodium bicarbonate and CH2Cl2. The aqueous phase was
decanted and extracted twice with 10 mL of CH2Cl2. Com-
bined organic phases were washed with brine, dried over
magnesium sulfate and concentrated under reduced pressure.
The resulting solid was dissolved in a mixture of 2-butanone
and isopropanol, and a saturated solution of HCl in ether was
added. The solvent was removed, the solid was recrystallized
from isopropanol to afford the solid hydrochloride, 575 mg,
27. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Mary-
anoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
28. Dardoise, F.; Goasdoue, C.; Goasdoue, N.; Laborit,
H. M.; Topall, G. Tetrahedron 1989, 45, 7783.
29. Typical procedure for the coupling with chloroacetyl
chloride. 14 derivative: 4-[(2-chloroacetyl)-(3,4-dichloro-
phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester.
7.00 g (20 mmol) of the corresponding compound of type 6
(R1=3,4-dichloro-phenyl) were dissolved in 250 mL of
CH2Cl2, 11.20 g (80 mmol) of potassium carbonate were
added and the mixture was cooled to 0 ꢂC. 9.16 g (80 mmol) of
chloroacetyl chloride were added, and the mixture was stirred
overnight. The reaction was quenched by addition of a solu-
tion of 6.8 g of sodium bicarbonate in 100 mL of water, the
aqueous phase was decanted and extracted twice with 50 mL
of CH2Cl2. Combined organic phases were washed with brine,
dried over magnesium sulfate and the solvent was removed
under reduced pressure. The resulting residue was triturated
with hexane. The product was obtained as a pink solid, 7.86 g,
yield 93%. C18H23Cl3N2O3=421.75, 1H NMR (CDCl3), d
(ppm) 1.3 (m, 2H), 1.4 (s, 9H), 1.8, (m, 2H), 2.8 (m, 2H), 3.6, (s,
2H), 4.2 (m, 2H), 4.6 (m, 1H), 7.1 (dd, 1H), 7.3 (d, 1H), 7.6 (d,
1H). 13C NMR (CDCl3), d (ppm): 28.6 (C(CH3)), 30.5
(NCH(CH2)2), 41.2 (BOCN(CH2)2), (COCH2Cl), 54.2 (NCH),
80.1 (OC(CH3)) 129.9, 131.8, 132.3, 134.0, 134.4, 137.1 (C aro-
matics), 154.7 (OCON), 165.9 (CCON). MS (LC–MS, APCI)
MH+ꢀBOC=321 (100%), 323, 325.
ꢂ
1
yield 88%. C21H24Cl2N2O2=407.34 g molꢀ1, mp 220 C, H
NMR (DMSO-d6), d (ppm): 1.50 (m, 2H), 1.9 (m, 2H), 2.2 (s,
6H), 2.9 (m, 2H), 3.3 (m, 2H), 4.3 (s, 2H), 4.6 (m, 1H), 6.4 (s,
2H), 6.6 (s, 1H), 7.4 (d, 1H), 7.7 (s, 1H), 7.8 (d, 2H). 13C N MR
(DMSO-d6), d (ppm): 21.2 (2 CH3), 26.7 (NCH(CH2)2), 40.4
(NCH ), 50.6 (N(CH2)2), 66.6 (OCH2CO), 112.6, 123.0, 131.0,
131.5, 132.0, 132.2, 132.6, 137.1, 138.8, 158.1 (aromatic C),
166.9 (CON). MS (LC–MS, APCI) MH+=407 (100%), 409,
411.
31. IAM chromatography: capacity factors (k0IAM) were
established on an IAM.PC.DD 2 Drug-Discovery HPLC Col-
umn 30ꢁ4.6 mm (Regis Tech Inc., Morton Grove, IL, USA).
The mobile phase consisted of different mixtures of phosphate
buffer saline (pH 7.4) and acetonitrile as co-solvent. The pub-
lished data are the extrapolated values at 0% in CH3CN.
32. Ong, S.; Liu, H.; Pidgeon, C. J. Chromatogr. A 1996, 728,
113.
33. Timmerman, H. Clin. Exp. Allergy 1999, 29 ( Suppl. 3), 13.
34. Patacchini, R.; Bartho, L.; Holzer, P.; Maggi, C. A. Eur.
J. Pharmacol. 1995, 278, 17.
35. Sharp, T. and Zetterstrom, T. In MonitoringNeural
¨
Activity; Oxford University: New York, 1992; p 147.
30. Compound 24 N-(3,4-dichloro-phenyl)-2-(3,5-dimethyl-
phenoxy)-N-piperidine-4-yl-acetamide. 1.95 g (6 mmol) of
cesium carbonate were suspended in 30 mL of Acetonitrile.
0.37 g (3 mmol) of 3,5 dimethylphenol was added and the