Pyrrolo[1,2-a]pyrazine and pyrazolo[1,5-a]pyrazine: Novel, potent, and selective series of Vasopressin1b receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.07.037

Novel series of pyrrole-pyrazinone and pyrazole-pyrazinone have been identified as potent and selective Vasopressin_1b receptor antagonists. Exploration of the substitution pattern around the core of these templates allowed generation of compounds with high inhibitory potency at the Vasopressin_1b receptor, including examples that showed good selectivity with respect to Vasopressin_1a, Vasopressin₂, and Oxytocin receptor subtypes.

Full text of DOI:10.1016/j.bmcl.2010.07.037

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5044–5049
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pyrrolo[1,2-a]pyrazine and pyrazolo[1,5-a]pyrazine: Novel, potent,
and selective series of Vasopressin1b receptor antagonists
Roberto Arban c, Federica Bianchi d, Alberto Buson e, Susanna Cremonesi a, Romano Di Fabio a,
a
a
b
a
Gabriella Gentile a, , Fabrizio Micheli , Alessandra Pasquarello , Alfonso Pozzan , Luca Tarsi ,
*
Silvia Terreni a, , Federica Tonelli
a
*
a Department of Medicinal Chemistry, GlaxoSmithKline, Neuroscience Centre of Excellence for Drug Discovery, Via A Fleming 4, 37135 Verona, Italy
b Computational and Structural Chemistry, GlaxoSmithKline, Neuroscience Centre of Excellence for Drug Discovery, Via A Fleming 4, 37135 Verona, Italy
c Department of Translational Biology, GlaxoSmithKline, Neuroscience Centre of Excellence for Drug Discovery, Via A Fleming 4, 37135 Verona, Italy
d PCDD&ET, GlaxoSmithKline, Neuroscience Centre of Excellence for Drug Discovery, Via A Fleming 4, 37135 Verona, Italy
e Screening and Compound Profiling, GlaxoSmithKline, Neuroscience Centre of Excellence for Drug Discovery, 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:
Novel series of pyrrole-pyrazinone and pyrazole-pyrazinone have been identified as potent and selective
Vasopressin1b receptor antagonists. Exploration of the substitution pattern around the core of these tem-
plates allowed generation of compounds with high inhibitory potency at the Vasopressin1b receptor,
including examples that showed good selectivity with respect to Vasopressin1a, Vasopressin2, and Oxyto-
cin receptor subtypes.
Received 16 June 2010
Revised 8 July 2010
Accepted 9 July 2010
Available online 14 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keyword:
Vasopressin1b receptor antagonists
Arginine vasopressin (AVP) and Oxytocin (OT) are nonapeptide
hormones released from the posterior pituitary into the blood
stream and their effects are mediated by four different G-protein
coupled receptor subtypes, Vasopressin1a (V1a), Vasopressin1b
(V1b), Vasopressin2, and Oxytocin.1
in mediating behavioral effects in response to stress needs to be
clarified since both peripheral9 and central sites10,11 have been
proposed to be involved in the anxiolytic and antidepressant-like
effects of V1b receptor antagonists. Therefore, the identification of
selective, orally bioavailable and brain penetrant V1b receptor
antagonists is an essential step to elucidate V1b receptor function
and to fully understand the therapeutic potential of molecules act-
ing at this target.
In this paper, we disclose the discovery of two novel series of po-
tent and highly selective vasopressin V1b receptor antagonists. The
2-(1-oxo-3-phenylpyrrolo[1,2-a]pyrazin-2(1H)-yl)acetamide (1)
and the 2-(4-oxo-6-phenylpyrazolo[1,5-a]pyrazin-5(4H)-yl)acet-
amide (2) derivatives (Fig. 1) were identified within our proprietary
compound collection as potent antagonists at the human V1b recep-
tor, with sub-micromolar potency and high selectivity with respect
In particular, the V1b receptor subtype is involved in the regula-
tion of adrenocorticotropin hormone (ACTH) release from the pitu-
itary gland, in the regulation of social behavior and in the
regulation of insulin release from the pancreas.2 Based on V1b
receptor function and distribution, selective V1b receptor antago-
nists have been suggested as potential therapeutic agents in the
treatment of diseases characterized by an excessive cortisol secre-
tion, such as major depression3 and stress-related disorders.4 The
first nonpeptidic V1b receptor antagonist, SSR149415, was discov-
ered in 20025 and its characterization in preclinical models consis-
tently supports the potential therapeutic benefits that may derive
from the blockade of V1b receptors in stress-related disorders.6
However, the selectivity of SSR149415 has been challenged since
a remarkable affinity for the human OT receptor has been re-
ported.7 More recently, a novel selective V1b receptor antagonist
has been identified and characterized in vitro and in vivo.8 Not-
withstanding, the role of peripheral versus central V1b receptors
O
O
N
N
O
O
H
H
N
N
O
O
N
N
N
N
N
Cl
Cl
* Corresponding authors. Tel.: +39 0458219355; fax: +39 0458218196 (G.G.); tel.:
+39 0458218052; fax: +39 0458218196 (S.T.).
1
2
E-mail addresses: gabriella.f.gentile@gsk.com (G. Gentile), silvia.p.terreni@gsk.-
com (S. Terreni).
Figure 1. Structures of compounds 1 and 2.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.037

R. Arban et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5044–5049
5045
Table 1
In Scheme 2, treatment of the commercially available 4,4,4-tri-
chloroacetoacetate with hydrazine hydrochloride in ethanol under
reflux afforded the desired 3-ethoxycarbonyl-5-hydroxypyrazole,
with simultaneous transformation of the trichloromethyl group
into carboxyl group.14 The hydroxyl moiety in the C-5 position of
the pyrazole intermediate was alkylated with [(3-bromopro-
pyl)oxy](1,1-dimethylethyl)dimethylsilane and, subsequently, the
nitrogen of the pyrazole derivative was alkylated with the appro-
priate 2-bromo-1-aryl-ethanone. Cyclization with ammonium ace-
tate under reflux afforded the required pyrazolo[1,5-a]pyrazine
derivative, where the tert-butyldimethylsilyl protecting group
was replaced by the acetate group. Alkylation with 2-chloro-N-iso-
propylacetamide readily allowed the introduction of the amide
side chain and the acetate group was removed under basic hydro-
lysis conditions. Reaction with methanesulfonyl chloride followed
by amine displacement afforded the desired final product.15
Starting from compounds 1 and 2, a structure–activity relation-
ship (SAR) exploration was carried out. Initial efforts were focused
on analogs of compound 1 in order to investigate the role of the
substitution pattern on the aryl moiety in the bottom left portion
of the molecule (Fig. 2 and Table 2, compounds 3–9). When the
chlorine was moved to the C-2 position a reduction of inhibitory
potency at the V1b receptor (compound 3) was observed, whereas
in the C-3 position both a methoxy group and a fluorine (com-
pounds 4 and 5) were tolerated. 3,4-Disubstitution (compounds 6
and 7) proved to be beneficial for the inhibitory potency at the
V1b receptor, whereas 3,6-substitution (compounds 8 and 9)
proved to be detrimental. SAR exploration of the aromatic portion
of compound 2, exemplified by the synthesis of some key com-
pounds, showed similar results (Fig. 2 and Table 2, compounds
10–12). Additional analogs of compound 2 were prepared and
the trifluoromethoxy group in the C-3 position highlighted a
reduction of inhibitory potency at the V1b receptor as did the intro-
Profiling results for compounds 1 and 2
a
a
a
a
Compound
V1b pIC50
V1a pIC50
V2 pIC50
OT pIC50
1
2
8.0
7.8
<4.3
<4.3
<4.5
<4.5
<4.3
<4.3
a
Data are expressed as means of 2–9 experiments, standard error of the mean
(SEM) is <0.1.
to V1a, V2, and OT receptor subtypes (Table 1). Compounds 1 and 2
were tested in a fluorescent imaging plate reader (FLIPR) Ca2+ func-
tional assay, measuring inhibition of vasopressin stimulated intra-
cellular calcium mobilization in CHO cells stably transfected with
the human V1b receptor; data were analyzed with IDBS Activity Base
software and results are expressed as pIC50
.
The discovery of compounds 1 and 2 prompted the synthesis of a
series of 2-(1-oxo-3-phenylpyrrolo[1,2-a]pyrazin-2(1H)-yl)acetam-
ide and 2-(4-oxo-6-phenylpyrazolo[1,5-a]pyrazin-5(4H)-yl)acetam-
ide derivatives which were prepared following the synthetic routes
outlined in Schemes 1 and 2, respectively. In Scheme 1, methyl 4-for-
myl-1H-pyrrole-2-carboxylate was easily prepared in good yield
exposing methyl 1H-pyrrole-2-carboxylate to Vilsmeier conditions.
Subsequently, the nitrogen of the pyrrole derivative was alkylated
with the appropriate 2-bromo-1-aryl-ethanone. The aldehyde group
was transformed into a hydroxyl group, following a modified Baeyer–
Villiger procedure12 and then the hydroxyl group was alkylated with
[(3-bromopropyl)oxy](1,1-dimethylethyl)dimethylsilane. Cycliza-
tion with ammonium acetate under reflux afforded the desired pyr-
rolo[1,2-a]pyrazine derivative, which was treated under basic
hydrolysisconditionstoremovetheprotectinggroup. Alkylationwith
2-chloro-N-isopropylacetamide readily allowed the introduction of
the amide side chain. Reaction with methanesulfonyl chloride fol-
lowed by amine displacement afforded the desired final product.13
O
CHO
O
Br
CHO
Rx
MeO
N
MeO
MeO
O
N
H
N
a
b
H
O
O
Rx
OTBDMS
O
OH
O
O
MeO
MeO
N
N
HN
O
O
O
O
c
N
d
e, f
Rx
OH
Rx
Rx
O
O
O
O
O
N
N
N
H
H
H
N
N
Cl
O
O
N
N
h
Rx
g
Rx
N
OH
Scheme 1. Reagents and conditions: (a) Vilsmeier reagent (POCl3, DMF, rt, 30 min), DMF, rt, 16 h; (b) K2CO3, CH3CN, rt, 1 h; (c) 1—m-CPBA, DCM, TFA, rt, 6 h; 2—MeOH,
Na2CO3 (2 N), rt, 5 min; (d) K2CO3, NaI, BrCH2CH2CH2OTBDMS, CH3CN, rt, 1 h; (e) NH4OAc, AcOH, 110 °C, 24–36 h; (f) LiOH, water, rt, 2 h; (g) K2CO3, CH3CN, 85 °C, 16 h; (h) 1—
methanesulfonyl chloride, TEA, DMAP, CHCl3, rt, overnight; 2—K2CO3, piperidine, DMF, 65 °C, 8 h.

5046
R. Arban et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5044–5049
OTBDMS
O
OH
O
O
EtO
EtO
N
N
Cl3C
OEt
N
N
a
b
H
H
O
O
O
OTBDMS
O
Br
Rx
O
EtO
N
HN
N
O
O
O
N
O
d
N
c
Rx
O
Rx
O
HN
O
HN
O
O
O
Cl
N
e
N
N
O
O
N
N
f
N
N
Rx
Rx
N
OH
Scheme 2. Reagents and conditions: (a) EtOH, NH2NH2ꢀHCl, 85 °C, 48–60 h; (b) Na2CO3, BrCH2CH2CH2OTBDMS, DMF, 60 °C, 18 h; (c) Na2CO3, DMF, 60 °C, 1.5 h; (d) NH4OAc,
AcOH, 100 °C, 24 h; (e) 1—NaH, NaI, DMF, 70 °C, 6 h; 2—LiOH, THF, rt, 3 h; (f) 1—methanesulfonyl chloride, TEA, DMAP, CHCl3, rt, overnight; 2—K2CO3, piperidine, DMF, 65 °C, 8 h.
Table 3
Profiling results for amide SAR, compounds 15–20
O
N
O
a
R1
V1b pIC50
H
Compound
Y
N
15
16
17
18
19
20
Cl
Cl
Cl
OMe
OMe
OMe
1,1-Dimethylethyl
Cyclopropylmethyl
Cyclobutyl
Ethyl
Cyclopropyl
8.6
7.2
7.2
6.1
6.7
6.4
O
N
X
R
N
Figure 2. SAR for alternative aryl substitutions.
2,2,2-Trifluoroethyl
a
Data are expressed as means of 3–10 experiments, SEM is <0.2.
Table 2
Profiling results for aryl substitutions SAR, compounds 3–14
a
Compound
X
R
V1b pIC50
O
O
3
4
5
6
7
C
C
C
C
C
C
C
N
N
N
N
N
2-Chlorophenyl
3-Methoxyphenyl
3-Fluorophenyl
6.1
7.9
7.1
8.4
8.3
7.0
7.1
7.8
8.4
8.3
6.4
6.8
N
N
O
O
H
H
N
N
O
O
3-Chloro-4-fluorophenyl
3-Trifluoromethyl-4-fluorophenyl
3-Chloro-6-fluorophenyl
3-Chloro-6-methylphenyl
3-Methoxyphenyl
3-Trifluoromethyl-4-fluorophenyl
3-Chloro-4-fluorophenyl
3-Trifluoromethoxyphenyl
3-Chloro-2-fluorophenyl
N
N
N
N
N
N
8
9
Cl
Cl
10
11
12
13
14
21
22
Figure 4. Variation in alkyl chain length on the RHS.
a
Data are expressed as means of 3–10 experiments, SEM is <0.2.
Table 4
Profiling results for alkyl chain vari-
ation, compounds 21–22
a
R1
O
Compound
V1b pIC50
21
22
6.5
6.0
N
O
N
O
N
a
Data are expressed as means of
4 experiments, SEM is <0.2.
N
Y
Figure 3. Exploration of substituents in the amide side chain.
duction of a fluorine in the C-2 position when a chlorine was pres-
ent in the C-3 position (compounds 13 and 14).

R. Arban et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5044–5049
5047
Table 6
Profiling results for alternative RHS SAR, compounds 28–35
O
N
O
a
R4
V1b pIC50
H
Compound
N
28
29
30
31
32
33
34
35
4-Piperidinyl
1-Methyl-4-piperidinyl
6.7
7.2
7.2
8.3
5.9
5.9
6.2
6.3
R3
O
N
N
1-(1-Methylethyl)-4-piperidinyl
1-Cyclopentyl-4-piperidinyl
(1-Methyl-4-piperidinyl)methyl
2-(1-Methyl-4-piperidinyl)ethyl
2-(1-Methyl-2-piperidinyl)ethyl
(1-Methyl-3-piperidinyl)methyl
R2
Cl
Figure 5. SAR exploration of alternative amines.
a
Data are expressed as means of 2–5 experiments, SEM is <0.2.
Table 5
Profiling results for amine SAR, compounds 23–27
NR2R3
V1b pIC50
a
Compound
O
N
O
23
24
25
26
27
3-Fluoro-1-piperidinyl
3-(Trifluoromethyl)-1-pyrrolidinyl
4-(Trifluoromethyl)-1-piperidinyl
(8aS)-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl
(8aR)-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl
8.0
8.2
8.2
7.2
6.7
H
N
O R4
N
a
Data are expressed as means of 3–4 experiments, SEM is <0.2.
Cl
Figure 6. SAR for alternative RHS chains.
Based on their similar in vitro profiles compounds 1 and 4 were
used as starting points to explore the SAR of the amide portion on
the left upper region of the molecule (Fig. 3 and Table 3). Dealing
with the substitution pattern when the isopropyl was replaced
with the 1,1-dimethylethyl group an increase of inhibitory potency
at the V1b receptor (compound 15) was observed, whereas cyclo-
propyl methyl and cyclobutyl groups as well as the cyclopropyl
moiety led to a reduction of the pIC50 value (compounds 16, 17,
and 19). In addition linear substituents (compounds 18 and 20)
were not very well tolerated.
O
N
O
H
R5
N
N
R6
N
Cl
Variation in the length of the alkyl chain on the right hand side
(RHS) of compound 2 negatively impacted inhibitory potency at
the V1b receptor (Fig. 4 and Table 4).
Figure 7. SAR exploration of N-linked chain derivatives.
As far as the SAR exploration of the RHS was concerned, an
exploration of alternative amines was carried out starting from
compound 1. Retaining the O-linked linear side chain, the piperi-
dine was replaced with amines with reduced basicity due to the
presence of an electron withdrawing group in the beta or gamma
position relative to the nitrogen, affording compounds with similar
inhibitory potency at V1b receptors to compound 1 (Fig. 5 and Table
5, compounds 23–25). However, when the piperidine was replaced
with piperazine derivatives a 10-fold drop in potency was ob-
served (compounds 26 and 27).
Further chemistry efforts were devoted to the RHS SAR expan-
sion synthesizing derivatives of compound 1 where alternative
spacers between the oxygen and the terminal nitrogen were
explored.
HO
OH
O
O
N
N
MeO
Boc
MeO
Boc
N
N
a
O
O
O
Cl
Cl
O
N
O
H
O
N
O
H
Cl
N
HN
d, e, f
b, c
O
O
N
N
N
N
Cl
Cl
Boc
33
Scheme 3. Reagents and conditions: (a) PPh3, diethyl azodicarboxylate, THF, rt, 5 h; (b) NH4OAc, AcOH, 110 °C, 24 h; (c) (Boc)2O, DCM, rt, 12 h; (d) NaH, NaI, DMF, 65 °C, 16 h;
(e) TFA, DCM, rt, 30 min; (f) formaldehyde, NaCNBH3, THF/MeOH (1:1), rt, 30 min.

5048
R. Arban et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5044–5049
O
O
I
Br
O
Ar
I
N
Cl3C
Cl3C
N
H
N
H
a
O
b
O
Cl
HN
O
O
HN
O
N
O
O
R5
N
N
I
N
N
e
I
c
R6
N
d
N
Cl
Cl
Cl
Scheme 4. Reagents and conditions: (a) I2, CF3COOAg, rt, 4 h; (b) K2CO3, DMF, rt, 6 h; (c) NH4OAc, AcOH, 110 °C, 24–36 h; (d) NaH, NaI, ClCH2C(O)NHiPr, DMF, 65 °C, 16 h; (e)
K2CO3, CuI, DL-proline, DMSO, amine, 80 °C, 24 h.
Table 8
Table 7
Pharmacokinetic parameters in rat for com-
Profiling results for N-linked chain SAR, compounds 36–49
pound 11 (iv dose: 1 mg/kg; po dose: 3 mg/kg)
a
Compound
NR5R6
V1b pIC50
Clb (mL/min/kg)
t1/2 (h)
Vd (l/kg)
43
2.9
9.6
69
774
78
36
37
38
39
40
41
42
43
44
45
46
47
48
49
4-Methyl-1-piperazinyl
6.6
7.9
7.2
5.9
6.3
5.4
8.3
8.2
7.3
6.3
5.9
6.7
6.2
6.9
4-Methylhexahydro-1H-1,4-diazepin-1-yl
4-(Dimethylamino)-1-piperidinyl
3-(Dimethylamino)-1-piperidinyl
3-(Dimethylamino)-1-pyrrolidinyl
4-[2-(Dimethylamino)ethyl]-1-piperidinyl
1,40-Bipiperidin-10-yl
4-(1-Pyrrolidinyl)-1-piperidinyl
Methyl(1-methyl-4-piperidinyl)amino
1-Methyl-1,7-diazaspiro[4.4]non-7-yl
9-Methyl-2,9-diazaspiro[5.5]undec-2-yl
2-Methyl-2,8-diazaspiro[4.5]dec-8-yl
2,7-Diazaspiro[3.5]non-7-yl
F (%)
AUC (h ng/mL)
Cmax (ng/mL)
Brain/blood ratio
0.95
oxoethyl]-4-hydroxy-1H-pyrrole-2-carboxylate, prepared as de-
scribed in Scheme 1, the side chain was introduced via Mitsunobu
reaction using the appropriate alcohol. Cyclization with ammo-
nium acetate under reflux afforded the desired pyrrolo[1,2-a]pyra-
zine with untimely deprotection of the amine functionality. Before
introduction of the amide chain by alkylation of the pyrrolo[1,2-
a]pyrazine core with 2-chloro-N-isopropylacetamide, the amine
group was re-protected with Boc-anhydride. The desired products
were obtained after deprotection and methylation of the amine
moiety by reductive amination with formaldehyde.13
2-Methyl-2,7-diazaspiro[3.5]non-7-yl
a
Data are expressed as means of 2–7 experiments, SEM is <0.3.
Table 6 shows potency data collected for the aforementioned
compounds. Good inhibitory potency at the V1b receptor was ob-
served only when replacing the linear chain with a O-4-piperi-
dine-N-substituted moiety (Fig. 6 and Table 6, compounds 29–31).
With the aim to further explore the RHS SAR of compound 1, the
O-linked alkyl chain was replaced with a variety of N-linked alkyl
chains (Fig. 7).
The desired N-linked derivates were prepared according to the
route outlined in Scheme 4. This involved preparation of 2,2,2-tri-
chloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone by iodination of a com-
mercially available starting material. One pot alkylation of the
nitrogen and cyclization gave the 3-chlorophenyl-7-iodo-1H-pyr-
rolo[2,1-c][1,4]oxazin-1-one derivative, that was converted into
the required 3-chloro-phenyl-7-iodopyrrolo[1,2-a]pyrazin-1(2H)-
one by heating at reflux in presence of ammonium acetate in acetic
acid. The amide side chain was readily introduced by alkylation
with 2-chloro-N-isopropylacetamide. Copper iodide catalyzed
cross-coupling, in the presence of DL-proline as ligand, afforded
the desired products.13
The results of this exploration are reported in Table 7. Nitrogen
as well as oxygen was tolerated as the linker. The highest potency
values at the V1b receptor were observed for compounds 42, 43,
and 37, while spiro derivatives 45–49 showed low to moderate
inhibitory potency. In order to rationalize the SAR for this series
Figure 8. V1b antagonist seven points pharmacophore with superimposed struc-
tures 15, 29, 37, 43, and 44. The pharmacophore contains the key features that are
common to some of the more active pyrrolo pyrazines. The RHS of the pharma-
cophore contains two pharmacophoric points (aromatic and positive ionizable) and
there is a certain level of tolerance in the way those two points are aligned. On the
other hand the LHS seems to be much more strictly defined and constrained. Of the
five most relevant pharmacophoric points two (the hydrogen bonds acceptors) have
also a precise spatial directionality.
The majority of the compounds bearing these alternative RHS
chains, were prepared following the route outlined in Scheme 3
for compound 33. Starting from methyl 1-[2-(3-chlorophenyl)-2-

R. Arban et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5044–5049
5049
of molecules, a pharmacophoric model16 was built using molecules
Supplementary data
15, 29, 37, 43, and 44 (Fig. 8). In fact, it was quite evident that the
position of the terminal nitrogen on the RHS in compounds 43 and
37, was superimposable with the position of the terminal nitrogen
in the linear chain of compound 15.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.07.037.
The in vitro pharmacology profile of many exemplars of both ser-
ies proved to be very attractive. In addition, the developability pro-
file of both series was encouraging; both metabolic stability
(Intrinsic Clearance, Cli) and CyP450 inhibition profiles for many
compounds appeared promising. Based on the in vitro pharmacol-
ogy of the different compounds, compound 11 was selected for
in vivo pharmacokinetic studies in the rat.17 Compound 11 as lead
exemplar of the pyrazolo[1,5-a]pyrazine series proved to be selec-
tive towards V1a, V2, and OT receptor subtypes (pIC50 V1a < 4.3,
pIC50 V2 < 4.5, andpIC50 OT < 4.7). Inadditioncompound11wassub-
mitted to the Cerep ‘Comprehensive Pharmacological Profile’ panel,
including 154 biological targets (GPCRs, ion channels, transporters
and enzymes), where it produced less than 50% displacement of
References and notes
1. Jard, S.; Barberis, C.; Audigier, S.; Tribollet, E. Prog. Brain Res. 1987, 72, 173.
2. Lee, B.; Yang, C.; Chen, T. H.; Al-Azawi, N.; Hsu, W. H. Am. J. Physiol. Endocrinol.
Metab. 1995, 269, 32.
3. Scott, L. V.; Dinan, T. G. Life Sci. 1998, 62, 1985.
4. Aguilera, G.; Rabadan-Diehl, C. Regul. Pept. 2000, 96, 23.
5. Serradeil-Le Gal, C.; Wagnon, J.; Simiand, J.; Griebel, G.; Lacour, C.; Guillon, G.;
Barberis, C.; Brossard, G.; Soubrie, P.; Nisato, D.; Pascal, M.; Pruss, R.; Scatton,
B.; Maffrand, J. P.; Le Fur, G. J. Pharmacol. Exp. Ther. 2002, 300, 1122.
6. Griebel, G.; Stemmelin, J.; Gal, C. S.; Soubrie, P. Curr. Pharm. Des. 2005, 11, 1549.
7. Griffante, C.; Green, A.; Curcuruto, O.; Haslam, C. P.; Dickinson, B. A.; Arban, R.
Br. J. Pharmacol. 2005, 146, 744.
8. Craighead, M.; Milne, R.; Campbell-Wan, L.; Watson, L.; Presland, J.; Thomson,
F. J.; Marston, H. M.; MacSweeney, C. P. Prog. Brain Res. 2008, 170, 527.
9. Shimazaki, T.; Iijima, M.; Chaki, S. Eur. J. Pharmacol. 2006, 543, 63.
10. Stemmelin, J.; Lukovic, L.; Salome, N.; Griebel, G. Neuropsychopharmacology
2005, 30, 35.
binding or inhibition at 1 lM in the full panel.
Furthermore, the PK profile of compound 11 proved to be accept-
able with moderate blood clearance and high volume of distribution,
high oral bioavailability and good brain penetration (Table 8).
In summary, we identified a novel series of potent vasopressin
11. Salome, N.; Stemmelin, J.; Cohen, C.; Griebel, G. Psychopharmacology (Berl)
2006, 187, 237.
12. Hickman, Z. L.; Sturino, C. F.; Lanchance, N. Tetrahedron Lett. 2000, 41, 8217.
13. Di Fabio, R.; Gentile, G.; Micheli, F.; Pasquarello, A.; Pozzan, A.; Tarsi, L.; Terreni,
S.; Tonelli, F. WO2009/130231.
14. Martins, M. A. P.; Pereira, C. M. P.; Zimmermann, N. E. K.; Moura, S.; Sinhorin, A.
P.; Cunico, W.; Zanatta, N.; Bonacorso, H. G.; Flores, A. C. F. Synthesis 2003, 15,
2353.
15. Di Fabio, R.; Gentile, G.; Pozzan, A.; Tarsi, L.; Terreni, S.; Tonelli, F. WO2009/
130232 .
16. The common feature pharmacophore was built using Catalyst (2009) as
implemented into the Discovery Studio platform. Conformers were generated
using the FAST algorithm and defaults settings. The best hypothesis is the one
depicted in the paper.
17. All the works involving animals were carried out in accordance with European
directive 86/609/EEC governing animal welfare and protection, which is
acknowledged by Italian Legislative Decree No. 116, 27 January 1992, and
according to internal review performed by the GlaxoSmithKline Committee on
Animal Research & Ethics (CARE) and to the company Policy on the Care and
Use of Laboratory Animals.
V1b receptor antagonists within which key exemplars showed high
selectivity with respect to V1a, V2, and OT receptor subtypes. The
best example selected from the series herein described, showed
high selectivity over an extensive range of GPCRs, ion channels,
transporters and enzymes. Moreover, this selected compound
exhibited a promising pharmacokinetic profile, including good
CNS penetration. Compounds from these series therefore deserve
to be further explored in vivo to exploit the therapeutic potential
of selective V1b receptor antagonists for human diseases.
Acknowledgments
The authors thank Dr. Mauro Pavan and Dr. Ornella Perini from
analytical group in Verona and Dr. Dino Montanari and his DMPK
group for the support received.