Design and synthesis of potential dual NK1/NK3 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2013.12.033

The tachykinin NK₁ and NK₃ receptors are a novel drug target for schizophrenia in order to treat not only the positive and cognitive symptoms, but also the associated co-morbid depression and sleep disturbances associated with the di

Full text of DOI:10.1016/j.bmcl.2013.12.033

Bioorganic & Medicinal Chemistry Letters 24 (2014) 510–514
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of potential dual NK1/NK3 receptor antagonists
a
a,
Stephen Hanessian a, , Vincent Babonneau , Nicolas Boyer , Clotilde Mannoury la Cour b,
⇑
Mark J. Millan b, Guillaume De Nanteuil c
a Department of Chemistry, Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, Que. H3C 3J7, Canada
b Department of Psychopharmacology, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy/Seine, France
c Neuroscience Chemistry Research Unit, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The tachykinin NK1 and NK3 receptors are a novel drug target for schizophrenia in order to treat not only
the positive and cognitive symptoms, but also the associated co-morbid depression and sleep
disturbances associated with the disease. A novel class of peptidomimetic derivatives based on a versatile
phenylglycine central core was synthesized and tested in vitro as dual NK1/NK3 receptor antagonists.
From this series emerged compounds with good NK1 receptor affinity, although only modest dual
NK1/NK3 receptor affinity was observed with one of these analogs.
Received 22 November 2013
Revised 4 December 2013
Accepted 9 December 2013
Available online 15 December 2013
Keywords:
Schizophrenia
Ó 2013 Elsevier Ltd. All rights reserved.
Neurokinin receptors
Peptidomimetic
NK1/NK3 receptor antagonists
Schizophrenia is a severe, lifelong, devastating mental disorder
that affects approximately 1% of the world population and is
among the world’s top ten causes of long-term disability.1 Clinical
symptoms are characterized by the presence of positive, negative
and mood symptoms, as well as cognitive impairment. Current
antipsychotic therapies (D2/5-HT2A receptor antagonists) are effec-
tive against positive symptoms but have a poor efficacy in the
treatment of negative and cognitive symptoms. Furthermore, these
drugs suffer from serious side effects and a high non-responder
rate.2
Mammalian tachykinins (also known as neurokinins, NK) are a
family of structurally related neuropeptides which are mainly
distributed in the central (CNS) and peripheral (PNS) nervous sys-
tems.3 This group of endogenous neuromodulators is characterized
by a common C-terminal sequence: Phe–X–Gly–Leu–Met–NH2
where X is either an aromatic or a branched aliphatic amino acid
residue.4 They affect a large number of biological activities5 such
as smooth muscle contraction and relaxation, immune system
function, pain transmission, and neurogenic inflammation. They
are also involved in various CNS disorders such as Parkinson’s,
Huntington’s, and Alzheimer’s diseases, depression, anxiety, and
psychosis.6 These neurotransmitters are mainly represented by
three major neuropeptides: substance P, (SP) and neurokinin A
(NKA), originating from the same gene (TAC1), and neurokinin B
(NKB) cleaved from the TAC3 gene.7 These oligopeptides are the
major endogenous ligands for the three human neurokinin recep-
tor subtypes, termed NK1R, NK2R and NK3R, belonging to the large
seven-transmembrane G protein-coupled receptor family.4,8 While
tachykinins are not specific for any individual NK receptor subtype,
they do have differing affinities (NK1R: SP > NKA > NKB; NK2R: NKA
> NKB > SP; NK3R: NKB > NKA > SP).
NK1 receptors (NK1R) are highly expressed in the CNS.9a Biolog-
ical and preclinical studies suggest that NK1R activation is closely
related to depression and anxiety, and that NK1R blockade would
therefore elicit both behavioral and physiological effects associated
with antidepressant and anxiolytic activities.9 Clinical trials in
humans indicate that selective NK1 receptor antagonists are effec-
tive in treating chemotherapy-induced emesis (Aprepitant™, 1)
(Fig. 1).10
NK3 receptors (NK3R) are almost exclusively found in the CNS
(e.g., cortical regions, amygdala, hippocampus, mild-brain).11 In
vitro and in vivo studies suggest that NK3R activation results in
the release of biogenic monoamines (i.e., dopamine, serotonine
and noradrenaline). Consequently, it has been hypothesized that
NK3R blockade with a selective antagonist could reduce the excit-
atory activation of dopaminergic, serotonergic and noradrenergic
systems and be associated with antipsychotic properties.12 Thus,
NK3R antagonism represents an alternative therapeutic approach
for the treatment of schizophrenia.
Recent data from clinical trials of Osanetant™ (2)13 (Fig. 1) and
Talnetant (3)14 as selective NK3R antagonists in schizophrenia
show significant improvement in positive symptoms (i.e., delu-
sions, hallucinations, and behavioral disorders), with no major
⇑
Corresponding author.
E-mail address: stephen.hanessian@umontreal.ca (S. Hanessian).
Current address: Ra Pharmaceuticals, Inc., One Kendall Square, Suite B14301,
Cambridge, MA 02139, United States.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.033

S. Hanessian et al. / Bioorg. Med. Chem. Lett. 24 (2014) 510–514
511
Figure 1. Reference structures of different NK1, NK3, and dual NK1/NK3 receptor antagonists.
side-effects reported as yet.12,15 However, no unequivocal activity
in the treatment of negative symptoms (i.e., anhedonia, anergia,
avolition and loss of spontaneity) was observed.16 In this context,
scientists at Hoffmann-La Roche laboratories have described piper-
idine (4) and spiropiperidine (5) derivatives as potent tachykinin
NK3 receptor antagonists for the treatment of schizophrenia.17
Derivative 6 is a relevant example of dual NK1/NK3 receptor antag-
onist17e,g (NK1R: pKi = 7.88; NK3R: pKi = 7.14) (Fig. 2). Taken to-
gether these results provide a rationale for the combination of
NK1 and NK3 receptor antagonism in order to provide a therapeutic
benefit for positive, negative, and mood symptoms associated with
schizophrenia, while having an improved side effect profile.18,19
In this context, we initiated a research program focusing on the
development of a novel series of dual peptidomimetic NK1/NK3
receptor antagonists where a phenylglycine is used as a versatile
building block for a fragment-based approach in lead discovery,
combined with the 3,5-[bis(trifluoromethyl)phenyl] acetic acid
substructure, thus resulting in residue identification and optimiza-
tion (Fig. 2).20
deprotection under acidic conditions. Hydroxyethyl analog (S)-13
was prepared by monoalkylation of amine (S)-12f with chloroeth-
anol and K2CO3 in DMF in poor yield (7%) due to double alkylation
as a competitive side reaction. 2-Morpholinoethyl intermediate
(S)-14 was further modified to include the variously substituted
arylacetic acids 10b–f to afford final products (S)-15b–f in good
overall yields (63–79%). A similar sequence was also followed for
the enantiomers (R)-11a and (R)-11e starting from N-Cbz-
D-phen-
ylglycine (R)-7.
We then focused our attention on the corresponding N-methyl
analog of 11a. Starting from N-Cbz- -phenylglycine (S)-7,
N-methyl- -phenylglycine (S)-17 was obtained by the regioselec-
L
L
tive cleavage of the corresponding oxazolidinone 16 using the
reducing system triethylsilane–trifluoroacetic acid (Et3SiH/TFA)
as reported by Freidinger and co-workers (Scheme 2).22 Liquid-
phase peptide coupling between acid 17 and 2-morpholino-ethan-
amine 8a, using DEPBT, afforded intermediate 18 in 57% yield.
Palladium-catalyzed hydrogenolysis and coupling with 2-[3,5-
bis(trifluoromethyl)phenyl]-2-methylpropionyl chloride afforded
the final product 19 in low yield (18%), with recovery of the
starting amine, possibly due to steric hindrance.
Preliminary in vitro pharmacological evaluation of these ana-
logs delineated some trends toward NK1R antagonism (Table 1).
Thus, a 2-morpholinoethyl appendage in combination with a
gem-dimethyl group and a 3,5-bis(trifluoromethyl)aryl moiety
(R4 = Me; R5 = CF3) proved beneficial (entries 2 vs 12 and 2 vs
13–15). Removal of the gem-dimethyl groups (R4 = H) resulted in
a slight diminution of activity, an effect exacerbated when com-
bined with the deletion of the trifluoromethyl substituents
(entry16). It appeared that the presence of a N-methyl phenylgly-
cyl subunit (R2 = Me) is well-tolerated and even beneficial for
the NK1R activity (entries 2 vs 6). Acyclic 2-aminoethyl and
2-(methylamino)ethyl side chains (entries 9 and 10) as well as cyc-
lic 2-morpholinoethyl and 2-(4-methylpiperazin-1-yl)ethyl groups
(entries 2, 4, 6, 12 and 17) showed good NK1R activity. The possible
In this Letter, we present the synthesis, biochemical data and
structure–activity relationship (SAR) studies focusing on the mod-
ulation and optimization of substitutions R1, R2, R3, R4 and R5 of the
central core. We began with the synthesis of the key intermediate
secondary amines 9a–g to enable the rapid exploration of the SAR
of the acid and amine moieties (Scheme 1). The readily available
N-Cbz-L-phenylglycine (S)-7 was coupled with several commer-
cially available or easily prepared amines 8a–g using 3-(diethoxy-
phosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT)21 in order
to minimize racemization at the acidic C -position. Compounds
a
(S)-11a–e were obtained in two steps from (S)-9a–e via deprotec-
tion of the N-terminus by hydrogenolysis followed by an amide
coupling reaction with 2-[3,5-bis(trifluoromethyl)phenyl]-2-meth-
ylpropanoic acid 10a. Intermediates (S)-9f–g, bearing a N-Boc-pro-
tected ethylamino chain, afforded final compounds (S)-12f–g via
N-Cbz removal, DEPBT-mediated coupling with 10a, and N-Boc
CF3
R5
O
F
Me
O
N
N
CF3
Phenylglycine
R3
Me Me
N
series
N
R5
NK1
pharmacophore
R4 R4
O
Me
N
OH
R1
R2
Stereochemistry
(aromatic moiety)
F
F
Amino chain
(basic site)
4
Hoffmann–La Roche
Figure 2. Drug design of dual NK1/NK3 receptor antagonists.

512
S. Hanessian et al. / Bioorg. Med. Chem. Lett. 24 (2014) 510–514
CF3
R2
N
R2
N
O
a
b, c
R1
NHCbz
9a–g
R1
N
H
CF3
HO2C
NHCbz
)-7
Me Me
O
O
(
11a–e
S
R1, R2 = see Table 1
b, c, d
O
b
CF3
H
N
H
R
N
N
H
N
H
CF3
N
NH2
Me Me
O
O
O
12f
14
: R = H
12g R = Me
:
e
f
CF3
R5
O
O
H
H
HO
N
N
N
H
N
H
CF3
N
N
R5
H
Me Me
R4 R4
O
13
O
O
15b–f
R4, R5 = see Table 1
Amines:
H
NH2
NH2
N
N
N
8b
Boc
N
NH2
O
N
Me
O
MeN
O
8a
8c
8d
NH
8e
NH2
Me
NH2
N
H
N
O
Boc
8f
8g
Acids:
CF3
CF3
CH3
Cl
HO2C
HO2C
HO2C
Me Me
HO2C
CF3
CF3
CH3
Cl
Me Me
10a
Me Me
10b
10c
HO2C
10d
HO2C
Me Me
10e
10f
Scheme 1. Reagents and conditions: (a) Amine 8a–g, DEPBT, Hünig’s base, CH2Cl2, rt, 16 h, 39–68%; (b) H2 (1 atm), Pd(OH)2/C (10 wt %), MeOH, rt, 16 h; (c) Acid 10a, DEPBT,
Hünig’s base, CH2Cl2, rt, 24 h, 50–80% (2-steps); (d) 4 M HCl in dioxane, dioxane, rt, 48 h, 80–90%; (e) Only for 12f to 13: 2-choroethanol, K2CO3, DMF, 80 °C, 3 d, 7%; (f) Acid
10b–f, DEPBT, Hünig’s base, CH2Cl2, rt, 16 h, 63–79%.
a
b
c
(S)-7
Cbz
O
Cbz
HOOC
N
N
O
Me
16
17
CF3
d, e
O
H
N
H
N
Cbz
N
N
N
N
CF3
Me Me
O
O
Me
O
O
Me
19
18
Scheme 2. Synthesis of the N-methyl analog of 11a. Reagents and conditions: (a) Paraformaldehyde, CSA, toluene, reflux, 30 min, 81%; (b) TFA/CHCl3 (1:1, v/v), Et3SiH, rt, 2 h,
79%; (c) 2-morpholinoethanamine 8a, DEPBT, Hünig’s base, CH2Cl2, rt, 18 h, 57%; (d) H2 (1 atm.), Pd(OH)2/C (10 wt %), MeOH, rt, 18 h, 97%; (e) 2-[3,5-bis(trifluoro-
methyl)phenyl]-2-methyl-propionyl chloride, Hünig’s base, CH2Cl2, rt, 3 h, 18%.
relevance of stereochemistry was reflected in the preference for a
(S)-phenylglycyl moiety over the enantiomeric (R)-analogs with a
ten-fold decrease (entries 2 vs 3 and 7 vs 8). The length of the side
chain also appeared critical, since a one-carbon extension resulted
in a dramatic drop in both NK1 and NK3 antagonism (entries 2 vs
5). The same trend was observed with a 2-(hydroxyethyl)amino-
ethyl chain (entries 9 and 10 vs 11). In spite of the promising
NK1R antagonism observed in this series of peptidomimetics, best
shown by analog (S)-19 (entry 17, NK1R: pKi = 7.78; NK3R:
pKi = 5.0), poor NK3R activity was exhibited by all the analogs with

S. Hanessian et al. / Bioorg. Med. Chem. Lett. 24 (2014) 510–514
513
Table 1
Dual affinities of compounds 6, 11a–e, 12f–g, 13, 15b–f and 19 for the human NK1 and NK3 receptors
R5
R2
O
N
R1
R5
N
R3
O
R4 R4
Entry
1
Compound
R1
—
R2
—
R3
—
R4
—
R5
—
pKi
NK1
7.9
a
b
NK3
7.1
(S)-6
N
2
3
(S)-11a
(R)-11a
H
H
H
H
CH3
CH3
CF3
CF3
7.0
5.6
6.0
<5
O
00
N
4
5
6
(S)-11b
(S)-11c
(S)-11d
H
H
H
H
CH3
CH3
CH3
CF3
CF3
CF3
6.6
<5
5.0
<5
MeN
O
H
N
N
CH3
7.1
5.0
O
7
8
(S)-11e
(R)-11e
–(CH2)2O(CH2)2–
H
H
CH3
CH3
CF3
CF3
6.5
5.6
<5
<5
00
9
(S)-12f
(S)-12g
H
H
H
H
CH3
CH3
CF3
CF3
6.5
6.6
5.0
5.0
H2N
10
MeHN
HO
N
11
12
(S)-13
H
H
H
H
CH3
H
CF3
CF3
<5
<5
H
N
(S)-15b
6.1
5.0
O
00
13
14
15
16
17
(S)-15c
(S)-15d
(S)-15e
(S)-15f
(S)-19
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
H
CH3
Cl
H
H
CF3
<5
<5
<5
<4
7.8
<5
<5
5.0
<5
5.0
00
00
00
00
CH3
CH3
Evaluation of the binding affinity (pKi) of compounds at both (a) human NK1 receptor and (b) human NK3 receptor was done using [125I]-Bolton Hunter-Substance P and [3H]-
SR142801 as radioligands, respectively. Data represent n = 2 independent determinations performed in duplicate; SD <0.2 pKi.2
6. Quartara, L.; Altamura, M.; Evangelista, S.; Maggi, C. A. Exp. Opin. Invest. Drugs
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pKi = 6.0).
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In conclusion, we have prepared a series of analogs inspired by
the Hoffmann-La Roche pyridine derivative 6 using a phenylgly-
cine amino acid as a versatile central motif. Variation of the
R1–R5 groups and pharmacological evaluation of these analogs
revealed derivative (S)-11a as promising dual NK1/NK3 antagonist.
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The University de Montréal group thanks Institut de Recherches
Servier, NSERC and FQRNT (Québec) for financial support. The
excellent technical assistance of Marie-Christine Tang, Karine
Venne, and Alexandra Furtos (Mass Spectrometry Laboratory of
Université de Montréal) is gratefully acknowledged.
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Supplementary data
Supplementary data (experimental procedures and spectro-
scopic data) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.bmcl.2013.12.033.
15. Meltzer, H.; Prus, A. Drug Discovery Today 2006, 3, 555.
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