Dual NK1 antagonists - Serotonin reuptake inhibitors as potential antidepressants. Part 2: SAR and activity of benzyloxyphenethyl piperazine derivatives

Article abstract of DOI:10.1016/S0960-894X(02)00563-2

The synthesis, structure-affinity relationship and activity of benzyloxyphenethyl piperazine derivatives combining NK₁ antagonism and serotonin reuptake inhibition is described. Compound 7u was shown to be active in animal models of 5-HT reuptake inhibition and central NK₁ receptor blockade, and was demonstrated to be orally active in an integrated model sensitive to both mechanisms. This class of compounds potentially represents a new generation of antidepressants.

Full text of DOI:10.1016/S0960-894X(02)00563-2

Bioorganic & Medicinal Chemistry Letters 12 (2002) 3195–3198
Dual NK1 Antagonists—Serotonin Reuptake Inhibitors as
Potential Antidepressants. Part 2: SAR and Activityof
Benzyloxyphenethyl Piperazine Derivativesy
Thomas Ryckmans,a,* Olivier Berton,b Renee Grimee,b Thierry Kogej,a Yves Lamberty,b
a
Patrick Pasau,a Patrice Talagaa andChristophe Genicot
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
Received24 May 2002; accepted17 July 2002
Abstract—The synthesis, structure–affinity relationship andactivity of benzyloxyphenethyl piperazine derivatives combining NK
antagonism and serotonin reuptake inhibition is described. Compound 7u was shown to be active in animal models of 5-HT reup-
1
take inhibition andcentral NK receptor blockade, and was demonstrated to be orally active in an integrated model sensitive to
1
both mechanisms. This class of compounds potentially represents a new generation of antidepressants.
# 2002 Elsevier Science Ltd. All rights reserved.
Depression is reportedto affect up to 10% of the
population2 andis linkedwith a significant mortality.
Antidepressant therapies using tricyclics (such as imi-
pramine 1) or Selective Serotonin Reuptake Inhibitors
(SSRIs) such as fluoxetine 2 are efficacious in about
70% of patients but are associatedwith side effects such
as dry mouth andblurredvision for tricyclics, andgas-
trointestinal distress, anxiety, insomnia and sexual dys-
function for the SSRIs.
Several lines of research4,5 are being pursuedalong these
lines for the discovery of new antidepressants, as well as
non-monoaminergic approaches such as estrogen,6,7
CRF8À14 andNK
receptor ligands (Scheme 1).
15
1
Another common problem in current therapies is their
slow onset of action, since a delay of about 4 weeks is
normally observedbetween the beginning of the treat-
ment andalleviation of the symptoms. This edlay
appears to parallel the progressive desensitization of
somatodendritic 5HT1A receptors which in turn gradu-
ally increases serotoninergic function. 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.3,4
Scheme 1. First- and second-generation antidepressants.
Thus far, NK1 antagonists15À18 seem especially promis-
ing. Indeed, in an animal model of depression,19 NK1
antagonists have a faster onset of action than imipra-
mine (1). In clinical trials, two NK1 antagonists, MK-
(4) were reportedto have
20,21
86916 (3) andCP 122,721
robust efficacy in treating depression (Scheme 2).
yFor Part I, see ref 1.
*Corresponding author at present address: Department of Discovery
Chemistry, Pfizer Global Research andDevelopment ipc 432, Sand-
wich, Kent CT13 9NJ, UK. Tel.: +44-1304-643-735; fax: +44-1304-
651-987; e-mail: thomas_ryckmans@sandwich.pfizer.com
Scheme 2. NK1 antagonists: MK-869, CP 122,721 andcompound 5.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00563-2

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T. Ryckmans et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3195–3198
The mode of action of NK1 antagonists is now believed
to involve an indirect modulation of 5-HT function, via
Noradrenergic pathways.22,23 NK1 receptor knock-out
three component reaction30,31 between an arylboronic
acid, glycolaldehyde and the Boc-protected piperazine.
Enantiopure 6 were preparedby reaction of homochiral
phenylglycinols with the activated N-tosyl diethanola-
mine derivative. Alcohols 6 were then O-benzylatedand
deprotected to afford the corresponding compounds 7 in
racemic (7a–q) or enantiopure (7r–u) form (Scheme 3).
mice andwild-type mice treatedwith NK
have an attenuatedpresynaptic 5HT
antagonists
receptor
1
1A
function.23À25 The combination of serotonin reuptake
inhibition with NK1 antagonism (modulating 5HT1A
function) may thus leadto a new class of anti-
depressants with an improved onset of action and better
efficacy.
Results
The optimisation of a family of phenoxyacetamides
with dual affinities for the NK1 receptor andthe Sero-
tonin Reuptake Site has recently been reported,1 while
Modification of R1 while keeping R2 substitution con-
stant showedthat the NK receptor does not tolerates
1
4-substituents while affinities for the ST were slightly
improved( 7a, 7b). Substitution of the 3-position with
chloro- or methoxy- was beneficial to NK1r binding
(7c, 7e) but affinities for the ST were unaffected. Finally
2-substitution with a chloro group (7g) was foundto
improve affinities for the NK1r but again left affinities
for the ST unchanged. 3,4- and 2,3-Disubstitutions were
not beneficial (7i, 7j). We then turnedto modification of
R2 in order to improve affinity for the ST.
Merck has described in the patent literature compounds
26
claimedto have a similar profile.
We now report the
SAR andin vivo activity of benzyloxyphenethyl piper-
azine derivatives that similarly combine Serotonin
Reuptake Inhibition andNK antagonism.
1
Screening27À29 of NK1 antagonists from the UCB com-
poundcollection against the Serotonin Transporter (ST)
resultedin the identification, amongst others, of com-
pound 5 (Table 1), which displays excellent affinity for
the NK1 receptor but moderate affinity for the ST. This
compoundwas usedas a starting point for this work.
Substitution with small (7k) or large (7l) alkyl groups
ledto an overall loss of affinities. Monosubstitution
(7m) or disubstitution with the smaller fluoro atoms (7n)
ledto an important reduction of the affinities toward
NK1r while ST binding was greatly improved. Unsym-
metrical disubstitution with the 30-CF3, 50-F (7o) or 30-
bromo 50-iodo (7p) provided compounds with high affi-
nities for both targets. Trisubstitution (7q) was also
beneficial.
Chemistry
The key alcohols 6 were preparedby either substitution
of a bromo phenylacetic ester with the Boc-protected
piperazine followedby reudction, or by an efficient,
At this stage, enantiopure compounds bearing the 30,50-
dichloro and 30,50-dibromo substitution (7r–7u) were
prepared. Fortunately, in each case, the S enantiomers
displayed very high affinities toward both targets, while
Table 1. Affinities of compounds 2–7 for the NK1 receptor andthe
Serotonin Transporter (ST)
Compd
(configuration)
R1
R2
pIC50
a
pIC50
STa
NK1
b
2 fluoxetine
3 MK 869
5
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
—
—
—
4-F
—
—
—
8.2
—
10.0c
8.3
7.0
7.3
8.8
7.4
9.0
8.3
8.8
8.2
8.3
8.5
7.6
7.0
6.4
6.7
7.9
8.9
8.1
7.6
8.5
7.9
8.5
30, 50-di CF3
30, 50-di CF3
30, 50-di CF3
30, 50-di CF3
30, 50-di CF3
30, 50-di CF3
30, 50-di CF3
30, 50-di CF3
30, 50-di CF3
30, 50-di CF3
30, 50-di CF3
30, 50-di Me
6.6
6.8
7.0
6.6
6.5
6.7
6.7
6.7
6.6
6.7
6.5
4-OMe
3-Cl
3-iPr
3-OMe
2-F
2-Cl
2-OMe
3,4-di Cl
2,3-di F
—
d
—
30, 50-di Bu
6.0
8.1
9.1
7.8
7.6
8.2
7.9
8.6
7.5
8.0
t
—
—
—
—
—
—
—
—
7m
7n
7o
7p
30-Cl
30, 50-di F
30-CF3, 50-F
30-Br, 50-I
7q
10-OMe, 30, 50-di Br
30, 50-di Cl
7r (R)
7s (S)
7t (R)
7u (S)
30, 50-di Cl
30, 50-di Br
30, 50-di Br
—
—
aValues are means of two experiments.
bLess than 50% inhibition at 10À5 M.
cSee ref 32.
Scheme 3. Preparation of benzyloxyphenethyl piperazines: (a) BOC-
piperazine, K2CO3, DMF, rt; (b) LiBH4, THF, reflux; (c) CH2Cl2, rt;
(d) Et3N, DMF, 80 ꢀC; (e) NaH, THF, Benzyl bromide, NaI, 60 ꢀC; (f)
TFA–CH2Cl2; (g) AcOH–HBr, 90 ꢀC.
dNot tested.

T. Ryckmans et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3195–3198
3197
the R enantiomers provedto be inferior. Compounds 7s
and 7u were selectedfor further examination in vivo.
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To assess the central 5-HT reuptake blockade properties
of the compounds, we tested their ability to increase
extracellular 5-HT levels in the frontal cortex of freely
moving rats by using intracerebral microdialysis.33
Intraperitoneal administration of 7u (3.2ꢁ10À5 mol/kg,
n=2) increased5-HT levels up to 250% of baseline for
more than 3 h. In this model, 7s was foundto be poorly
active, possibly because of metabolic instability or lim-
itedbrain penetration. Activity of 7u as a NK1 antago-
nist was assessedusing the gerbil foot-tapping model as
described by Rupniak.34 At the dose of 3.2ꢁ10À5 mol/
kg (ip, n=5), 7u decreased by 45% the duration of the
foot-tapping, indicating efficacious central blockade of
NK1 receptors. Finally, in the isolation-induced guinea
pig pup vocalization test, an integratedbehavioural
model sensitive to both SSRI and NK1 antagonists,35 7u
was shown to be orally active, as it was able to attenuate
by 50% (1ꢁ10À5 mol/kg, n=8) and99% (3.5 ꢁ10À5
mol/kg, n=8) the duration of vocalizations.
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In conclusion, we were able to optimise a family of
benzyloxyphenethyl piperazines to the level of fluox-
etine for the ST, with an added affinity for the NK1
receptor. One of the best compounds in this family was
shown to be active in animal models indicative of 5-HT
reuptake inhibition andcentral NK receptor blockade,
1
and was demonstrated to be orally active in an validated
animal model of depression sensitive to both mechanisms.
Further developments in this area will be reported in
due course.
Acknowledgements
The authors wish to thank Marie-Agnes Lassoie for
initial preparation of racemic 7t–u, Reiner Dieden and
Alain Fauconnier for their skillful analytical assistance,
Bruno Fuks andMichel Gillardfor the in vitro binding
measurements, Corinne Audouin for follow-up of the
manuscript andLuc Que re for fruitful discussions.
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