Synthesis and pharmacological characterization of constrained analogues of Vestipitant as in vitro potent and orally active NK1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2009.11.078

A focused exploration targeting conformationally restricted analogues of Vestipitant, resulted in the discovery of novel, in vitro potent NK₁ antagonists. In particular, two of the compounds reported exhibited a good pharmacokinetic (PK) profile and produced anxiolytic-like effects in the gerbil foot tapping (GFT) in vivo model.

Full text of DOI:10.1016/j.bmcl.2009.11.078

Bioorganic & Medicinal Chemistry Letters 20 (2010) 623–627
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and pharmacological characterization of constrained analogues
of Vestipitant as in vitro potent and orally active NK1 receptor antagonists
*
*
Fabio M. Sabbatini , Romano Di Fabio , Cristiana Griffante, Giorgio Pentassuglia , Laura Zonzini,
Sergio Melotto, Giuseppe Alvaro, Anna M. Capelli à, Lara Pippo §, Elisabetta Perdona’, Yves St. Denis,
Silvano Costa, Mauro Corsi
Neurosciences Centre of Excellence for Drug Discovery and Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A focused exploration targeting conformationally restricted analogues of Vestipitant, resulted in the dis-
covery of novel, in vitro potent NK1 antagonists. In particular, two of the compounds reported exhibited a
good pharmacokinetic (PK) profile and produced anxiolytic-like effects in the gerbil foot tapping (GFT)
in vivo model.
Received 14 September 2009
Revised 13 November 2009
Accepted 17 November 2009
Available online 20 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The neurokinin-1 (NK1a) receptor is a 7TM G-protein coupled
receptor (GCPR) known to be implicated in the pathophysiology
of a range of pathological conditions, namely: inflammatory bowel
disease, pain, migraine, movement disorders, schizophrenia, sleep
disorders, emesis, nausea, anxiety and depression.1 In particular,
the NK1 receptor antagonists MK-8692 and CP-122,721,3 shown
in Figure 1, were proven to possess antidepressant activity in clin-
ical trials performed by Merck and Pfizer, respectively, whereas
GR205171 showed anxiolytic-type activity in social phobia.4
Moreover, MK-869 (Aprepitant)5 is currently on the market for
the treatment of post-operative and chemotherapy-induced nau-
sea and vomiting.
tor antagonists.6 In particular, Vestipitant (Fig. 1) showed
appropriate pharmacokinetics and excellent anxiolytic-like behav-
iour in the gerbil foot tapping (GFT) in vivo model, after oral
administration. As part of a wider exploration performed within
this chemical series, and with the aim of expanding our knowledge
in terms of the pharmacophoric requirements of the arylpiperazine
template, we sought to introduce some elements of rigidity within
this template (Fig. 2).
This was achieved either by introducing a conformational con-
strain, tethering the nitrogen atom to the adjacent arylpiperazine
As a consequence of their large therapeutic potential, the iden-
tification of novel non-peptide, potent and brain penetrant NK1
receptor antagonists is still perceived within the medicinal chem-
istry community as an important target to achieve. Recently, we
reported the preparation and the pre-clinical profile of a novel ser-
ies of phenylpiperazine derivatives as potent drug-like NK1 recep-
CF3
MeO
CF3
O
N
O
N
H
N
H
N
F
HN
O
NH
Abbreviations: NK, neurokinin; 7-TM, 7-transmembrane; SP, substance P; GPCR,
G-roteincoupled receptor; CNS, central nervous system; SAR, structure–activity
relationship; CDI, arbonyldiimidazole; THF, tetrahydrofuran; DMF, dimethylform-
amide; DCM, dichloromethane; BOC, tert-butoxycarbonyl; TEA, triethylamine;
MsCl, mesyl chloride; TFA, trifluoroacetic acid; CHO, Chinese Hamster Ovary; FLIPR,
fluorescence imaging plate reader; GFT, gerbil foot tapping.
* Corresponding authors. Tel.: +39 045 9218946; fax: +39 045 8218196 (F.M.S.);
tel.: +39 0458218879; fax: +39 045 8218196 (R.D.F.).
E-mail addresses: Fabio.M.Sabbatini@GSK.com (F.M. Sabbatini), rdf26781@
gsk.com (R.D. Fabio).
CP-122721
MK-869
MeO
CF3
CF3
H
N
N
N
N
N
N
N
CF3
N
H
O
N
Present address: E-Pharma Trento SpA, Via Provina 2, 38040 Ravina di Trento,
Trento, Italy.
H
F
à
Present address: Molecular Discovery Research, Computational and Structural
GR205171
Vestipitant
Sciences, GlaxoSmithKline Medicines Research Centre, Verona, Italy.
§
Present address: GSK SpA, Via Fleming 2, 37139 Verona, Italy.
Figure 1. Some examples of potent NK1 antagonists described in the literature.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.078

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F. M. Sabbatini et al. / Bioorg. Med. Chem. Lett. 20 (2010) 623–627
cyclize (A, B)
derivative 11 in high overall yield by sequential protection of the
primary amino group as BOC, mesylation reaction and nucleophilic
substitution with NaN3 in DMF at 80 °C. Then, the alkylation reac-
tion of the nitrogen with NaH and 3,5-bis-trifluoromethylbenzyl-
amine gave compound 12 which was reduced to give
intermediate 13. The following reaction afforded the lactam 14
which was transformed into the imidazolinone 17, as a single cis
diastereoisomer, by sequential imine reduction and removal of
the N-BOC protecting group followed by a cyclization reaction in
the presence of CDI. Finally, the chemoselective reduction of the
lactam function afforded the target compound 1.
HN
N
N
O
increase steric bulk (C)
F3C
CF3
F
A
C
H
CF3
B
N
CF3
HN
N
N
N
N
CF3
Preparation of the five-membered cyclic diastereoisomers 2a
and 2b is shown in Scheme 2. Condensation between the commer-
cially available ester 18 and the N-vinyl lactam 19 followed by
one-pot deprotection, lactam ring opening and rearrangement of
intermediate 20, afforded the cyclic imine 21, which was reduced
to form the corresponding amine 22 and then transformed into
the urea 23 as a mixture of diastereoisomers. Removal of the
N-BOC protecting group and separation of the two diastereoiso-
mers gave the final compounds 2a and 2b. The synthesis of the cor-
responding six-membered cyclized compounds 3a, 3b and 4a, 4b is
shown in Scheme 3. The commercially available carboxylic acid
derivative 24 was allylated at the benzylic position. Then, the fol-
lowing Curtius-type rearrangement afforded a mixture of the urea
intermediates 26a and 26b.
After smooth allylation of the urea nitrogen atom the diastere-
oisomers 27a and 27b were separated by flash chromatography.
Then, the ring closing metathesis reaction was carried out and
the desired cyclized compounds 28a and 28b, were smoothly ob-
tained from 27a and 27b, respectively.
Subsequent removal of the N-BOC protecting group afforded the
compounds 3a and 3b. Finally, hydrogenation of the double bond
gave title compounds 4a and 4b. The preparation of the bis-piper-
azine derivatives 5a and 5b is shown in Scheme 4. The commer-
cially available bromide 29 was smoothly acylated to give the
oxalate derivative 30, which was treated with ethylenediamine
to afford 31. After sequential reduction of the imine function and
the lactam, the 2-arylpiperazine intermediate 33 was obtained.
The less hindered amino atom was chemoselectively protected as
BOC. Ureas 35a and 35b were then formed in the presence of the
O
CF3
HN
O
F
X
N
N
F
CF3
6
1
O
F3C
F
2a-5a
2b-5b
Figure 2. Constrained analogues of Vestipitant.
nucleus (A) forming appropriate five- or six-membered rings (B) or,
as an alternative, making the benzylic position quaternary (C).
Herein, we describe the synthesis of the novel compounds de-
signed, along with their structure activity relationship (SAR). In
addition, the pharmacokinetics and in vivo activity in the GFT
model of some selected compounds, are also reported.
Compound 1 was prepared as shown in Scheme 1. Commer-
cially available 1-amino glycerol 8 was transformed into the azido
c
b
N3
NHR
HO
NHR
NHR
MsO
N3
OH
OMs
10
8 R = H
11
a
9 R = BOC
d
CF3
e
CF3
H2N
N
R
N3
N
R
NH2
N3
CF3
13
CF3
N
12
COOMe
f
O
O
a
O
N
+
CF3
CF3
F3C
CF3
HN
N
HN
N
R
F3C
CF3
g
NH
R
N
O
O
19
18
20
CF3
CF3
15 R = BOC
16 R = H
h
b
F
F
14
i
R
N
HN
N
HN
N
N
N
H
N
N
N
N
l
O
c
d
CF3
O
O
CF3
O
CF3
F3C
CF3
F3C
F3C
CF3
F3C
F3C
F
F
F
21
22
1
17
23
R = BOC
e
Scheme 1. Reagents and conditions: (a) (Boc)2O, EtOH, 1 h, rt, 100%; (b) DCM, TEA,
0 °C, MsCl, rt, 300, 87%; (c) DMF, NaN3, 80 °C, 3 h, 82%; (d) NaH, DMF, 3,5-bis-
trifluoromethylbenzylamine, 0 °C, 1 h, 100%; (e) Pd/C 10%, MeOH, H2 (1 atm), 24 h,
97%; (f) EtOH, ethyl(4-fluoro-2-methylphenyl)(oxo) acetate, reflux, 24 h, 60%; (g)
Pd/C 10%, MeOH, H2 (1 atm), 3 h, 67%; (h) MeOH/HCl 37%, reflux, 3 h, 45%; (i) CDI,
DMF, 100 °C, 3 h, 76%; (l) BH3THF, 2 h, rt, then HCl, 26%.
2a, 2b R = H
Scheme 2. Reagents and conditions: (a) NaH, toluene, reflux, 12 h; (b) (i) HCl 6 N,
reflux, THF, 4 h; (ii) KOH; y = 5%; (c) NaBH4, MeOH, 0 °C, 1 h, y = 85%; (d) TEA,
triphosgene, MeCN, 1,1-dimethylethyl (3S)-3-(4-fluoro-2-methylphenyl)-1-pipera-
zinecarboxylate (7), rt, 2 h, reflux, 5 h, y = 56%; (e) MeOH, HCl, reflux, 2 h, y = 100%.

F. M. Sabbatini et al. / Bioorg. Med. Chem. Lett. 20 (2010) 623–627
625
CF3
chiral intermediate 7 and final removal of the N-BOC protecting
group followed by separation of the diastereoisomers gave the final
compounds 5a and 5b.
The synthesis of compound 6 is reported in Scheme 5. Hydrost-
annylation reaction of the commercially available methyl 2-propy-
noate 36 afforded intermediate 37, which was transformed into the
COOMe
MeOOC
Sn(Bu)3
b
a
CF3
38
H
COOMe
36
37
c
CF3
CF3
CF3
R
N
H
N
R
d
e
HOOC
F3C
HOOC
F3C
N
N
N
N
CF3
a
b
CF3
CF3
O
O
COOH
40
COOMe
CF3
CF3
CF3
R = BOC
26a, 26b
F3C
39
25
F
24
F
f
41 R = Boc
c
CF3
CF3
R
N
H
R
N
N
R
g
N
N
N
N
N
N
N
CF3
d
CF3
N
N
O
O
O
O
CF3
F3C
CF3
F3C
F
6
42
F
F
28a, 28b
27a, 27b
Scheme 5. Reagents and conditions: (a) Bu3SnH, Pd(PPh3)2Cl2, THF, rt, 100, y = 46%;
(b) DMF, 1-bromo-3,5-bis(trifluoromethyl)benzene, CuI, Pd-tetrakis, y = 21%; (c)
(Me)3SOI, NaH 60%, DMF, rt, 1 h, y = 16%; (d) LiOH, MeOH, reflux, 2 h, y = 100%; (e)
(PhO)2P(O)N3, TEA, 7, toluene, rt, 3 h, then 100 °C, 1 h, y = 56%; (f) MeI, t-BuONa,
THF, rt, 1 h, y = 100%; (g) MeOH, HCl 37%, reflux, 150, y = 54%.
e
H
H
N
N
N
N
O
N
N
f
O
CF3
F3C
CF3
vinylester derivative 38 by Stille-type coupling with commercially
available 1-bromo-3,5-bis(trifluoromethyl)benzene. Then the key
cyclopropanation reaction was performed according to Corey’s
conditions.7 Basic hydrolysis of the ester 39, followed by Curtius-
type rearrangement in the presence of the chiral arylpiperazine
derivative,8 gave intermediate 41. Sequential methylation of the
urea nitrogen atom and removal of the N-BOC protecting group
afforded the final compound 6.
The in vitro affinities of the compounds described above are
shown in Table 1. Compound 1 (cyclization A, Fig. 2) exhibited a
significant drop of affinity with respect to Vestipitant, most likely
as a consequence of the inappropriate spatial orientation of the
urea carbonyl group which, as observed from X-ray analysis of
Vestipitant,6 should lie out of the plane of the piperazine ring.
Conversely, cyclization of type B (Fig. 2) enabled us to identify 3b
as a novel compound retaining good in vitro affinity compared to
Vestipitant (pKi = 9.3 and 9.6, respectively), while the correspond-
ing saturated analogue 4b and the five-membered ring derivative
2b were found to be less active (pKi = 8.2 and 7.2, respectively).
Noteworthy, the introduction of an amino group within the satu-
rated six-membered ring was well tolerated (compound 5b,
pKi = 9.1); this result was particularly significant as for the first
time it was shown that the presence of an additional basic hetero-
atom on the right hand side of the template can be tolerated, sug-
gesting the possible presence of an additional pharmacophoric
point.
F3C
3a, 3b
F
F
4a, 4b
Scheme 3. Reagents and conditions: (a) BuLi, DIPEA, allyl bromide, THF, ꢀ78 °C,
y = 69%; (b) 7, TEA, (PhO)2P(O)N3, toluene, 3 h, rt, reflux, 1 h, y = 37%; (c) THF, allyl
iodide, t-BuONa, rt, 3 h, y = 58%; (d) DCM, rt, 3 h, Grubb’s catalyst ((benzyli-
dene)dichlorobis(tricyclohexylphoshine)ruthenium), y = 67% (diast. 1), y = 62%
(diast. 2); (e) (i) TFA/DCM, 300, rt; (ii) H2O, K2CO3; (iii) HCl 1 M, Et2O, 300, rt,
y = 58% (diast. 1), y = 59% (diast. 2); (f) (i) H2, Pd/C 10%, 1 Atm, rt, 3 h; (ii) TFA/DCM,
rt, 1 h; (iii) K2CO3/H2O; (iv) HCl 1 M, Et2O; y = 32% (diast. 1), y = 25% (diast. 2).
H
N
OEt
N
O
Br
O
O
a
b
CF3
CF3
CF3
CF3
CF3
CF3
31
29
30
c
H
O
R
R
R
N
N
N
N
N
N
N
N
H
f
H
d
O
CF3
CF3
CF3
CF3
CF3
F3C
F
Diastereoisomers 3a, 4a and 5a exhibited reduced in vitro affin-
ity with respect to 3b, 4b and 5b (pKi = 7.7, 7.5 and 7.0,
respectively).
32
33 R = H
34 R = BOC
R = BOC 35a, 35b
R = H 5a, 5b
g
e
Modelling studies using compound 1, the 2S,6R,-diastereoiso-
mer of compound 3a/3b (IUPAC name: (2S)-1-{[(6R)-6-[3,5-bis
(trifluoromethyl)phenyl]-3,6-dihydro-1(2H)-pyridinyl]carbonyl}-
2-(4-fluoro-2-methylphenyl)piperazine) and the 2S,2S-diastereo-
isomer of the compound 5a/5b (IUPAC name: (2S)-2-[3,5-bis
(trifluoromethyl)phenyl]-1-{[(2S)-2-(4-fluoro-2-methylphenyl)-1-
Scheme 4. Reagents and conditions: (a) (i) Mg, I2, Et2O, reflux, 3 h; (ii) diethyl
oxalate, ꢀ60 °C, rt, y = 63%; (b) NH2CH2CH2NH2, Na2SO4, toluene, reflux, 16 h,
y = 32%; (c) H2, Pd/C, MeOH, 1 atm, rt, 3 h, y = 100%; (d) (i) BH3 THF, reflux, 4 h, (ii)
HCl Et2O, 45 °C, 1 h, y = 67%; (e) (Boc)2O, TEA, 0 °C, 600, y = 100%; (f) triphosgene, 7,
TEA, rt, 1 h, y = 40%; (g) TFA, DCM, H2O, K2CO3, HCl Et2O, y = 48% (diast. 1), y = 30%
(diast. 2).

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F. M. Sabbatini et al. / Bioorg. Med. Chem. Lett. 20 (2010) 623–627
Table 1
In vitro affinity, measured by inhibition of the binding of [3H]-substance P ([3H]-SP) to
membranes obtained from Chinese Hamster Ovary cells transfected with human NK1
receptors (h-NK1 CHO)9
H
N
X
N
N
CF3
O
F3C
F
b
Compound
X
pKia
ID50
Vestipitant
1
2ª
—
—
(CH2)2
(CH2)2
CH2CH@CH
CH2CH@CH
(CH2)3
9.6
7.3
7.2
8.2
7.7
9.3
7.5
8.9
7.0
9.1
9.3
0.014
2b
3a
3b
4a
4b
5a
5b
6
(CH2)3
(CH2)2NH
(CH2)2NH
—
Figure 3B. Shape and pharmacophoric overlay of Vestipitant (ball&stick, colour by
atom type), the 2S,6R-diastereoisomer of compound 3a/3b (stick, yellow) and the
2S,2R-diastereoisomer of compound 5a/5b (stick, light blue).
0.4
0.2
a
pKi values are the mean of at least two experiments performed in duplicate. The
difference between the averaged pKi values was always lower than 0.3.
b
ID50 is the compound dose causing 50% inhibition of the tapping behaviour
stereochemistry of the two stereogenic centres and the in vitro
affinity to the NK1 receptor binding site not obvious. The slight
drop in potency exhibited by the five-membered ring derivatives,
exemplified by compound 2a/2b (Table 1), might be related to
the suboptimal orientation of their pendant phenyl rings.
Finally, compound 6, in which a quaternary centre was intro-
duced at the benzylic position, retained good potency compared
to Vestipitant (pKi 9.3 and 9.6, respectively). Two of the most
in vitro potent compounds, 5b and 6, were endowed with good
in vivo PK profile in the rat.11
Compound 5b, in rat, 5 min after administration, exhibited
acceptable brain penetration (B/P = 0.9). In addition a Cmax = 32
ng/mL and AUC(0–8 h) = 145 ng h/mL were observed at 1 mg/Kg,
po. Compound 6, instead, displayed increased brain penetration
(B/P = 4.0) and comparable exposure in plasma (Cmax = 29 ng/mL;
AUC(0–8 h) = 108 ng h/mL) after oral administration at 1 mg/kg.
When compound 5b was given sc, 1 h prior to icv infusion of the
NK1 agonist GR73632,12 a dose dependent inhibition of foot tap-
ping in gerbils was observed, with an estimated ID50 of 0.4 mg/
kg. Following the same protocol, compound 6 caused a dose depen-
dent inhibition of foot tapping in gerbils with an estimated ID50 of
0.2 mg/kg.
elicited by the icv injection of GR73632 (substance P), 3 pmol/5 lL to gerbils. ID50
values are expressed in mg/kg after oral or sc administration one hour before the
test.
piperazinyl]carbonyl}piperazine), resulted in the identification of
good shape and pharmacophoric 3D alignments.10 As shown in
Figure 3A these conformationally locked analogues are able to pro-
ject their common pharmacophoric features (i.e., the positive ion-
izable group corresponding to the secondary amine, the two
hydrophobic moieties mapped by the two phenyl rings and a
hydrogen bond-acceptor feature mapped by the carbonyl moiety)
into the same spatial area mapped by Vestipitant. Furthermore,
the accessory six-membered rings could be accommodated in a
common binding pocket. However, from this analysis, it cannot
be ruled out that they can lie in a different pocket as shown by
the 3D alignment of the 2S,2R-diastereoisomer of compound
5a/5b (IUPAC name: (2R)-2-[3,5-bis(trifluoromethyl)phenyl]-1-
{[(2S)-2-(4-fluoro-2-me thylphenyl)-1-piperazinyl]carbonyl}piper-
azine, Figure 3B), making the association of the relative
In conclusion, the design and the exploration of some conform-
ationally constrained analogues of Vestipitant enabled the identifi-
cation of novel in vitro and in vivo potent and brain penetrant NK1
receptor antagonists, exhibiting good drug-like properties. In par-
ticular, compounds 5b and 6 were shown to be active in vivo in
the GFT model. Furthermore, these findings contributed to a better
understanding of the pharmacophoric and structural requirements
of these series of NK1 antagonists.
Acknowledgements
The authors thank Dr. Carla Marchioro’s group for structural
and analytical support.
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