Phenylethynyl-pyrrolo[1,2-a]pyrazine: A new potent and selective tool in the mGluR5 antagonists arena

Article abstract of DOI:10.1016/j.bmcl.2008.02.024

The synthesis and the structure activity of a new series of pyrrolo[1,2-a]pyrazine is reported. These molecules are potent and selective non-competitive mGluR5 antagonists and may shed new light on the pattern of substitution tolerated by this receptor.

Full text of DOI:10.1016/j.bmcl.2008.02.024

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 1804–1809
Phenylethynyl-pyrrolo[1,2-a]pyrazine: A new potent
and selective tool in the mGluR5 antagonists arena
Fabrizio Micheli,* Barbara Bertani,* Andrea Bozzoli, Luca Crippa, Paolo Cavanni,
Romano Di Fabio, Daniele Donati, Paola Marzorati, Giancarlo Merlo, Alfredo Paio,
Lorenzo Perugini and Paola Zarantonello
GlaxoSmithKline, Psychiatry Centre of Excellence for Drug Discovery, Via Fleming 4, 37135 Verona, Italy
Received 24 January 2008; revised 8 February 2008; accepted 10 February 2008
Available online 14 February 2008
Abstract—The synthesis and the structure activity of a new series of pyrrolo[1,2-a]pyrazine is reported. These molecules are potent
and selective non-competitive mGluR5 antagonists and may shed new light on the pattern of substitution tolerated by this receptor.
Ó 2008 Elsevier Ltd. All rights reserved.
Glutamate is the main neurotransmitter within the cen-
tral nervous system (CNS) and it operates through dif-
ferent receptors. Some are ion channels (NMDA,
AMPA, and kainate receptors), while others are a pecu-
liar family of 7-Transmembrane (7-TM) G-protein-cou-
pled receptors (GPCRs), the metabotropic receptors
(mGluRs).1 Based on sequence homology, functional
coupling, and pharmacology, mGluRs are classified as
belonging to groups I, II, or III.2,3 Group I receptors
are primarily localized postsynaptically and consist of
subtype 1 (mGluR1) and subtype 5 (mGluR5), which
exhibit different patterns of expression in the CNS.
A number of different reviews have been recently pub-
lished on ligands acting on this family12,13 and it is evi-
dent that one of the most recurring structural motifs in
the field of mGluR5 non-competitive antagonists is the
acetylene linker,14–16 despite the fact that the triple bond
has sometime been suspiciously considered by some
medicinal chemists because of its potential liabilities
(e.g., phototoxicity or bio-activation potential). This
acetylene linker is also a key feature of a new high affin-
ity radioligand prepared for Positron Emission Tomog-
raphy (PET) recently disclosed.17 In this manuscript, the
identification of an alternative scaffold to the pyridine
MPEP nucleus is reported together with the associated
exploration which allows some further consideration
of the space available into the mGluR5 allosteric pocket.
The activation of the mGluR5 receptor is linked to the
stimulation of phospholipase C (PLC), leading to phos-
phoinositide (PI) hydrolysis and ultimately to an in-
crease of intracellular levels of Ca2+
.
Considering the relatively limited solubility of derivative
1 and its activity on some monoaminergic transport-
ers,18 the identification of alternative and highly
selective scaffolds was considered a priority in GSK to
further validate in vivo a number of the potential
One of the best known non-competitive antagonists is
surely represented by 6-methyl-2-(phenylethynyl)-pyri-
dine4 (MPEP; 1, Fig. 1), and by its close analogs, like
2.5,6 The modulation of mGluR5 receptor through this
type of derivatives has wide potential therapeutic appli-
cations in a variety of CNS disorders.7–11
NH2
N
N
F
Keywords: mGluR5; Metabotropic; 7-TM; Receptor; Antagonists.
*
2
1
Corresponding authors. Tel.: +39 045 8218515; fax: +39 045
8218196; e-mail: fm20244@gsk.com
Present address: Bayer,Viale Certosa 126, Milan, Italy.
Figure 1. mGluR5 non-competitive antagonists. MPEP (1), and its
close analog amino derivative from Addex Pharmaceuticals (2).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.02.024

F. Micheli et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1804–1809
1805
therapeutic applications claimed for the mGluR5 antag-
onists. Among the different approaches used to achieve
this target (ranging from HTS campaign to rational
drug design), the introduction of a novel ring attached
to the ethynyl moiety is described here.
The para position, on the other side, resulted to be quite
sensitive to electron-withdrawing (EWG) groups and to
steric hindrance; while the introduction of a Fluorine (5)
led to a 10-fold decrease in potency, the substitution
with a Chlorine (6) or a Bromine (7) led to poor or com-
plete loss of activity, respectively. The presence of the
hydroxyl derivative (8), even if in meta position, was
also detrimental. This effect might be associated to the
presence of a hydrogen donor (HD) group not tolerated
by the receptor. The detrimental effect onto this scaffold
of EWG systems was also evident replacing the phenyl
ring with a pyrimidine one (9) and, probably reinforced
by the steric clashes, with an isoquinolinyl moiety (10).
Working on the pyrrolo[1,2-a]pyrazine scaffold, the
introduction of a moderately EWG group like the tri-
fluoromethyl derivative in position 7 (12) was relatively
well tolerated and helped to demonstrate, like in the
MPEP series, the positive role of the methyl group in
position 3 (11) on the potency at the mGluR5 receptor.
In the same position 7, the slightly more EWG cyano
group (13) was, on the other hand, very well tolerated
leading to almost nanomolar potency. It was therefore
hypothesized that the EWG detrimental effect on the
scaffold might have been mitigated by the relative
hydrophilicity of the CN group.
Each of the new chemical entities (NCE) prepared was
tested for agonism and antagonists in a Fluorescent
Imaging Plate Reader (FLIPRTM) functional screen.19
Selectivity assays over mGluR1 and over representative
of group II and III mGluRs were performed on the
most interesting NCEs. Among the different alternative
nuclei identified, the exploration of the pyrrolo[1,2-
a]pyrazine scaffold is reported here as this template re-
sulted of particular interest: actually, the non-decorated
derivative 3 (Table 1) showed a potency comparable to
MPEP (1) in the same assay. The compound was com-
pletely selective over mGluR1 and over group II and
III mGluRs. Before starting an investment of chemical
resources on this template, its overall selectivity profile
was checked too. Compound 3 was therefore submitted
to a CEREP High-Throughput Profiling over 50 recep-
tors (test concentration 1 lM), including Noradrenaline
(NE) and Dopamine (DE) transporters showing no un-
wanted activities. The introduction of a methyl group
in meta position on the phenyl ring (4) lead to an al-
most 10-fold increase in potency, leading to sub-nano-
molar potency.
To test this hypothesis, different amides were prepared
(14–16). In this case, a reduction of potency was ob-
Table 1. Potency values for selected NCEs on h-mGluR5 receptor
R
Ar
N
N
R1
Compound
R1
R
Ar
pIC50
1
Not applicable
Not applicable
8.0
7.5
8.6
9.4
7.8
6.2
<4.9
6.5
5.7
<4.9
6.8
7.4
8.9
7.0
7.1
7.8
7.3
8.0
8.2
6.9
6.8
6.3
6.5
6.7
2
3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
Ph
3-Me-Ph
4
H
5
H
4-F-Ph
4-Cl-Ph
6
H
7
H
4-Br-Ph
3-OH-Ph
8
H
9
H
5-Pyrimidinyl
4-Isoquinolinyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
H
CF3
CF3
CN
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
(4-Methyl-1-piperazinyl) carbonyl
1-Pyrrolidinyl carbonyl
4-Morpholinyl carbonyl
CH3
COOEt
3-Methyl-1,2,4-oxadiazol-5-yl
CONHMe
1-Piperidinyl methyl
(4-Methyl-1-piperazinyl) methyl
4-Acetyl-1-piperazinyl) methyl
(3-Oxo-1-piperazinyl) methyl
IC50s are geometric means of at least three independent experiments.
The standard deviation is 0.3.

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F. Micheli et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1804–1809
Table 3. Potency values for selected NCEs on h-mGluR5 receptor
served, but this effect might have been also due to the
limited space available in this region of the receptor.
Actually, among the three amides, the more hydrophilic
(but not basic) morpholinyl derivative 16 was the best
tolerated. To continue the work around this hypothesis,
the introduction of an almost neutral methyl group (17)
resulted in a comparable potency to the –CF3 derivative
12, while the bulkier but more hydrophilic COOEt
derivative 18 increased the potency again, even if not
reaching the values of the cyano derivative. As the bulk-
iness of the amides (14–16) was spaced by one carbon
(the carbonyl group) from the scaffold, the introduction
of a sterically hindered, but hydrophilic group directly
linked to the template was attempted. The results
achieved by the oxadiazole (19) seem to strengthen the
hypothesis that hydrophilic and moderately hindered
derivatives are well tolerated in this region of the recep-
tor. As it happened on the aromatic ring for the phenolic
derivative 8, the presence of a hydrogen donor (HD)
group (or of an acidic proton) directly linked to the tem-
plate (20) resulted in a loss of potency. This was also ob-
served with the introduction of basic moieties (21–24)
independently of their pKb or steric hindrance.
F3C
R
N
N
Me
Compound
R
pIC50
12
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
H
7.4
7.1
3-OMe
3-CF3
3-F
6.5
7.8
3-Cl
3-Br
7.0
7.6
3-CN
7.9
3-NHSO2CH3
3-NHAc
3-COOH
3-COO-t-Bu
2-F
<4.9
6.1
<4.9
<4.9
6.9
2-Cl
2-CF3
5.3
<4.8
<4.8
7.0
2,4-bis F
4-F
4-Cl
5.7
The new scaffold also provided advantages in terms of
solubility. When measured at pH 7.4, derivative 1
showed in our conditions an average solubility – mea-
sured as a free base – of 70 lg/mL; under the same con-
ditions, derivatives 3 and 21 were endowed (as free base)
of a solubility of 165 and 100 lg/mL, respectively.
4-CF3
4-CN
<4.8
<4.8
<4.8
<4.8
4-NMe2
4-NHSO2CH3
IC50s are geometric means of at least three independent experiments.
The standard deviation is 0.3.
The next step of the exploration was related to a more
complete analysis of the aromatic region linked to the
ethynyl group. As clearly reported in Table 2, the substi-
tution of position 4 of the phenyl ring (25–28) was det-
rimental for potency (compared to 17) and also the
substitution in position 3 (29–31) was not very effective,
with the only tolerated groups being represented by the
–CF3 (29) and the thienyl compound 31, while the mod-
erate basicity of the pyridine moiety (30) led to a sensible
decrease of potency. A more extensive exploration was
performed on the trifluoromethyl scaffold 12 and the
results are reported in Tables 3 and 4. Also in this case,
meta substitution (32–37) of the phenyl ring was
Table 4. Potency values for selected NCEs on h-mGluR5 receptor
F3C
Ar
N
N
Me
Compound
Ar
pIC50
52
53
54
55
56
57
58
59
60
61
62
63
64
4-Pyridyl
2-Pyridyl
3-Pyridyl
7.1
7.3
6.3
1-Methyl-imidazol-5-yl
3-Furyl
2-Thienyl
<4.9
7.3
Table 2. Potency values for selected NCEs on h-mGluR5 receptor
7.2
8.0
3-Thienyl
Me
Ar
3-(1H-Pyrazol-4-yl)phenyl
3-(4-Isoxazolyl)phenyl
3-(1-Methyl-1H-pyrazol-4-yl) phenyl
3-(3,5-Dimethyl-4-isoxazolyl) phenyl
3-(3-Furanyl)phenyl
3-(3-Thienyl)phenyl
<4.9
6.1
N
N
<4.9
<4.9
5.0
Me
5.3
Compound
Ar
pIC50
IC50s are geometric means of at least three independent experiments.
The standard deviation is 0.3.
25
26
27
28
29
30
31
4-CF3
4-Cl
4-F
<4.8
<5.4
6.4
favoured over para-substituted analogs (46–51) with
the caveat that acidic or bulky groups were not tolerated
in this region (38–41).
4-CN
<4.8
6.8
3- CF3
3-Pyridyl
3-Thienyl
5.7
7.2
The replacement of the phenyl ring (12) with different
heterocycles (52–58) was generally tolerated with the
IC50s are geometric means of at least three independent experiments.
The standard deviation is 0.3.

F. Micheli et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1804–1809
1807
Table 5. Potency values for selected NCEs on h-mGluR5 receptor
exception of more basic/polar substitution (55). The 3-
thienyl derivative (58), in particular, reached remarkable
levels of potency keeping unchanged its original selectiv-
ity profile.
R
Ar
N
N
The attempt to exploit the ‘favoured’ meta position of
the phenyl ring to achieve higher potency values or to
introduce groups that might have potentially led to
more soluble derivatives gave poor results when different
heterocycles were inserted in this region (60–64).
Me
Compound
R
Ar
pIC50
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
CN
CN
2-F-phenyl
3-F-phenyl
3-CF3-phenyl
3-Thienyl
8.5
9.1
CN
CN
7.8
9.4
As this result was not related to the level of basicity/
acidity of the aromatic residues used, it might be corre-
lated to a possible steric clash of this region of the scaf-
fold within the mGluR5 receptor as previously observed
with the introduction of the bulky tert-butyl ester 41 in
the same region.
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
CONH2
CONH2
CONH2
3-Cl-phenyl
3-CF3-phenyl
3-CN-phenyl
4-CN-phenyl
7.7
6.7
8.5
<4.8
4-CF3-phenyl <4.8
4-Cl-phenyl
4-F-phenyl
2-F-phenyl
3-Thienyl
<4.8
6.4
6.5
8.1
5.8
6.3
7.1
7.3
5.8
7.0
6.7
7.3
6.6
7.7
6.8
7.7
6.9
7.7
7.9
8.0
5.9
Finally, to rapidly complete the exploration of position
7 of the pyrrolo[1,2-a]pyrazine in combination with the
pattern of substitution on the aromatic ring attached
to the ethynyl moiety in terms of potency at the mGluR5
receptor, a small combinatorial exploration was per-
formed and the results are reported in Table 5, high-
lighting the discovery of some very potent nanomolar
and sub-nanomolar derivatives. Derivative 71, when
submitted to an in-house profiling over 70 receptors (test
concentration 1 lM), confirmed complete selectivity at
the desired target for this template, with no activity on
the other mGluRs tested. More importantly, the po-
tency results achieved were not only limited to the smal-
ler and more hydrophilic substituents present in position
7 (CN, COOEt), but also confirmed the results already
observed with the more hindered 4-morpholinylcarbon-
yl substituent.
3-Pyridyl
2-F-phenyl
3-CF3-phenyl
3-Thienyl
CONHMe
CONHMe
CONHMe
CONHMe
2-F-phenyl
3-F-phenyl
3-CF3-phenyl
3-Thienyl
1-Pyrrolidinyl carbonyl
1-Pyrrolidinyl carbonyl
1-Pyrrolidinyl carbonyl
1-Pyrrolidinyl carbonyl
4-Morpholinyl carbonyl
4-Morpholinyl carbonyl
4-Morpholinyl carbonyl
4-Morpholinyl carbonyl
2-F-phenyl
3-F-phenyl
3-CF3-phenyl
3-Thienyl
2-F-phenyl
3-F-phenyl
3-CF3-phenyl
3-Thienyl
(4-Methyl-1-piperazinyl) 2-F-phenyl
carbonyl
To further explore this area and to complete the explora-
tion of the level of tolerance of mGluR5 receptor versus
the increase of steric bulk of amide moieties in position
7 of the pyrrolo[1,2-a]pyrazine scaffold, a small array
was prepared keeping fixed the thienyl portion. The re-
sults of this exploration are reported in Table 6 (deriva-
tives 98–105) and are in agreement with the results of
the previous small exploration (14–16). This area of the
scaffold seems to have a steric clash with the mGluR5
receptor even when a smaller 3-thienyl derivative is at-
tached on the template. In particular, while derivative
104 and 105 are not dramatically different from derivative
14–16, the increased bulkiness of the other groups (s, 98–
99) led to a greater reduction in potency.
95
96
97
(4-Methyl-1-piperazinyl) 3-F-phenyl
carbonyl
6.7
6.6
6.8
(4-Methyl-1-piperazinyl) 3-CF3-phenyl
carbonyl
(4-Methyl-1-piperazinyl) 3-Thienyl
carbonyl
IC50s are geometric means of at least three independent experiments.
The standard deviation is 0.3.
ing carboxylic acid intermediate V, allowing the synthe-
sis of differently substituted amides VI. When the amide
was a primary one, it could be transformed into the cor-
responding nitrile VII through reaction with phospho-
rous oxychloride and subsequently converted to the
final products using palladium coupling reactions.
All the NCEs described in this manuscript were pre-
pared in accordance to the general Scheme 1.
The pyrrolo[2,1-c][1,4]oxazin-1-one I20 was transformed
into the corresponding pyrrolo[1,2-a]pyrazin-1(2H)-one
II with acetic acid and ammonium acetate. Functional
group interconversion with phosphorous oxychloride al-
lowed the preparation of the versatile intermediate III
which was coupled under microwave (MW) conditions
with appropriately substituted aryl acetylenes in good
yields. The ethoxy carbonyl derivative III proved to be
very versatile; it could be hydrolyzed to the correspond-
Again, the COOEt derivative III could be directly trans-
formed into the oxadiazolyl derivative and coupled with
the acetylenic derivative to give derivative 19. Further-
more, direct reduction of the same ester with lithium
aluminum hydride led to the primary alcohol VIII. This
intermediate was coupled to give the desired ethynyl
derivatives IX and then transformed into the desired
amino derivatives using a ‘one pot’ reaction exploiting
supported reagents.

1808
F. Micheli et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1804–1809
Table 6. Potency values for selected NCEs on h-mGluR5 receptor
S
R
N
N
Me
Compound
R
pIC50
98
99
(1R,4S)-2-azabicyclo[2.2.1]hept-2-yl carbonyl
[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl] carbonyl
(2,2-Dimethyl-1-pyrrolidinyl) carbonyl
(3,3-Difluoro-1-pyrrolidinyl) carbonyl
6.2
5.4
5.9
6.9
6.4
6.5
7.4
7.0
100
101
102
103
104
105
(2,5-Dimethyl-1-pyrrolidinyl) carbonyl
[(2R,6S)-2,6-dimethyl-4-morpholinyl] carbonyl
(2-Methyl-1-pyrrolidinyl) carbonyl
(2-Methyl-1-piperidinyl) carbonyl
IC50s are geometric means of at least three independent experiments.
The standard deviation is 0.3.
competitive binding site of the mGluR5 receptor. In par-
ticular, the tolerability of certain regions to steric bulk
and hydrophilicity in position 7 of the new scaffold
was established.
R
R
R
R
Ar
O
O
Cl
N
N
N
N
a
c
b
O
N
N
N
3-10,12,
17, 25-64,
69-78
I
II
III
1
The exploration allowed the identification of com-
pounds endowed with sub-nanomolar potency (4, 66
and 68) and high selectivity versus both the mGluRs
family and other receptors including monoaminergic
transporters.
1
R
R
2
2
N
R
N
R
HOOC
Cl
EtOOC
O
O
Ar
Cl
Cl
e
d
N
c
N
N
N
N
N
N
N
III
V
Finally, a number of derivatives with improved solubil-
ity and acceptable potency were also identified and
helped to further validate the potential therapeutic
applications of the mGluR5 antagonists as will be re-
ported in due course.
VI
14-16, 20
79-105
i, c
f
NC
NC
19
g
Ar
Ar
Cl
c
N
N
N
N
1
13,65-68
R
VII
HO
Acknowledgments
HO
Ar
N
R
2
Cl
c
h
N
N
N
We thank Dr. Carla Marchioro and her analytical group
for the support received. Manuela Ciraco’, Fabio De
Giorgis, Elisabetta De Magistris, Alessandro Pontiroli,
and Nicoletta Savoretti for synthetic support. Elisa Bal-
lini, Alberto Buson, Sharon Butler and Magalie Roche-
ville for screening and assay development.
N
N
N
VIII
21-24
IX
Scheme 1. General condition for the preparation of the NCEs
previously described. Reagents and conditions: R = CF3, Me, H,
COOEt. (a) AcOH, NH4OAc; 160 °C, 48 h; (b) POCl3, reflux, 5 h; (c)
CuI, (PPh3)2PdCl2, HC„CAr, DMF, TEA, 120 °C, MW, 0.5 h; when
R = COOEt in intermediate III, then (d) NaOH, dioxane, H2O, 95 °C
MW, 0.2 h; (e) R1R2NH2, DIPEA, HATU, DMF. rt, overnight. When
intermediate VI has R1 = R2 = H, then (f) POCl3, CH3CN, reflux, 3 h;
when R = COOEt in intermediate III, then (g) LiAlH4, THF, from
0 °C–rt, 0.5 h; (h) supported PPh3, CBr4, CH2Cl2, rt, 2 h; followed by
R1R2NH, DIPEA, DMF, rt overnight; (i) N-hydroxyethanimidamide,
NaH, THF, rt, overnight.
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19. Activity is measured as the alteration of a glutamate
induced increase in intracellular calcium which activates a
fluorescent dye loaded into the cells. The fluorescence
produced is measured by FLIPRTM. Chinese Hamster
Ovary cells transfected with the h-mGluR5 receptor under
the control of the GeneSwitchTM Gene Expression appa-
ratus were used.
20. Derivatives of general formula I reported in Scheme 1
were prepared from the corresponding 4-substituted 2,2,2-
trichloro-1-(1H-pyrrol-2-yl)ethanone adding 1.2 equiv of
1-chloro-2-propanone and stirring the mixture in acetone
in the presence of K2CO3 at room temperature for 20 h,
followed by appropriate chromatographic separation
(CyH-AcOEt from 90/10 to 80/20).
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