Synthesis and SAR of substituted pyrazolo[1,5-a]quinazolines as dual mGlu2/mGlu3 NAMs

Article abstract of DOI:10.1016/j.bmcl.2014.04.051

Herein we report the design and synthesis of a series of substituted pyrazolo[1,5-a]quinazolin-5(4H)-ones as negative allosteric modulators of metabotropic glutamate receptors 2 and 3 (mGlu₂ and mGlu₃, respectively). Development of this series was initiated by reports that pyrazolo[1,5-a]quinazoline-derived scaffolds can yield compounds with activity at group II mGlu receptors which are prone to molecular switching following small structural changes. Several potent analogues, including 4-methyl-2-phenyl-8-(pyrimidin-5-yl)pyrazolo[1,5-a]quinazolin-5(4H)-one (10b), were discovered with potent in vitro activity as dual mGlu₂/mGlu₃ NAMs, with excellent selectivity versus the other mGluRs.

Full text of DOI:10.1016/j.bmcl.2014.04.051

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2693–2698
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of substituted pyrazolo[1,5-a]quinazolines as dual
mGlu2/mGlu3 NAMs
Cody J. Wenthur a,b, Ryan D. Morrison a,b, J. Scott Daniels a,b, P. Jeffrey Conn a,b, Craig W. Lindsley a,b,c,
⇑
a Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
b Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
c Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report the design and synthesis of a series of substituted pyrazolo[1,5-a]quinazolin-5(4H)-
ones as negative allosteric modulators of metabotropic glutamate receptors 2 and 3 (mGlu2 and mGlu3,
respectively). Development of this series was initiated by reports that pyrazolo[1,5-a]quinazoline-
derived scaffolds can yield compounds with activity at group II mGlu receptors which are prone to
molecular switching following small structural changes. Several potent analogues, including
4-methyl-2-phenyl-8-(pyrimidin-5-yl)pyrazolo[1,5-a]quinazolin-5(4H)-one (10b), were discovered with
potent in vitro activity as dual mGlu2/mGlu3 NAMs, with excellent selectivity versus the other mGluRs.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 25 March 2014
Revised 10 April 2014
Accepted 11 April 2014
Available online 20 April 2014
Keywords:
Metabotropic glutamate receptor 2
Metabotropic glutamate receptor 3
mGlu2 receptor
mGlu3 receptor
Negative allosteric modulator (NAM)
Since their discovery, the metabotropic glutamate receptors
(mGlus) have elicited a great deal of interest from the neurophar-
macology community, both in academia and in the pharmaceutical
industry. As a group, this family of GPCRs has been suggested to
represent a host of novel targets for the treatment of many of the
most prevalent psychiatric and neurodegenerative diseases.1–3
Within the mGlu family, the group II receptors, metabotropic gluta-
mate receptor 2 (mGlu2) and metabotropic glutamate receptor 3
(mGlu3) have received significant attention for their roles in the
treatment of schizophrenia, depression, anxiety disorders, and sub-
stance abuse.4–9
Early medicinal chemistry efforts, pioneered by Eli Lilly and Co.,
focused on the development of constrained-glutamate analogues
that could preferentially activate or inactivate the group II recep-
tors in comparison to the group I and group III mGlus.10,11 While
these compounds are among the most frequently used and widely
available tools to study group II mGlu function, independent lines
of anatomical, pharmacological, and electrophysiological evidence
suggest that mGlu2 and mGlu3 have separate, and in some cases,
competing functions.12–17 In order to more effectively elucidate
the individual functions of mGlu2 and mGlu3, there have been sev-
eral campaigns to develop compounds capable of discriminating
between these two receptors.
Many of the most successful efforts to develop such subtype-
selective ligands have targeted allosteric sites on mGlu2 or
mGlu3.18 These ligands bind at a distinct site from the orthosteric
pocket, and act to either potentiate signaling by the endogenous
ligand, in the case of positive allosteric modulators (PAMs) or to
diminish signaling by the endogenous ligand, in the case of nega-
tive allosteric modulators (NAMs).3,19 This strategy has led to the
development of several selective mGlu2 PAMs, and more recently,
selective mGlu3 NAMs.18,20,21 However, aside from claims in the
patent literature with minimal selectivity data, there have been
no formal reports of functionally-selective mGlu2 NAMs or mGlu3
PAMs.22 This lack of tool compounds represents a significant bar-
rier to progress in understanding the biological roles and therapeu-
tic relevance of these two receptors.
Recent disclosures have provided some evidence that pyrazol-
o[1,5-a]quinazolines can act as dual inhibitors of mGlu2 and mGlu3
in a DtectAll™ FRET-based binding assay system.23 Also, it has
been reported that mGlu2 NAMs, mGlu3 NAMs, and mGlu3 PAMs
have been developed via directed alterations to this chemotype
(Fig. 1A).24 Such molecular switching has been previously reported
for compounds targeting mGlu5, a group I mGlu, and compounds
targeting mGlu4, a group III mGlu, but there has been limited infor-
mation regarding the phenomenon amongst compounds targeting
group II mGlus.25–28
In order to improve understanding of the structure–activity
relationship (SAR) underlying molecular switching amongst group
II mGlus, several chemical libraries were developed around a
⇑
Corresponding author. Tel.: +1 615 322 8700; fax: +1 615 343 6532.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
http://dx.doi.org/10.1016/j.bmcl.2014.04.051
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

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C. J. Wenthur et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2693–2698
mGlu3
PAM
A
B
O
X
Alk
N
R3
mGlu2
NAM
mGlu3
NAM
N
R1
N
N
Ar
N
N
R2
Ar
1
2
Figure 1. (A) Structural alterations to a pyrazolo[1,5-a]quinazoline core have been
reported to result in mode switching. (B) Structural features selected for alteration
in library design to explore group II SAR.
pyrazolo[1,5-a]quinazoline-5(4H)-one core. These libraries focused
on alterations to three distinct areas of the molecule: aryl-substitu-
tions on the pyrazole ring, aryl-additions to the quinazoline, and N-
alkyl-substitutions on the quinazoline (Fig. 1B).
The initial compounds were synthesized using a matrix-library
strategy, where alterations at R1 and R2 were combined in order to
rapidly generate a large amount of structural diversity (Scheme 1).
Briefly, 2-amino-4-bromo-benzoic acid 3 is converted to the hydra-
zine 4, which is condensed with an array of substituted benzoyl-
acetonitriles under microwave conditions in order to form a
series of 8-bromo-pyrazolo[1,5-a]quinazolin-5(4H)-ones that are
differentially substituted at the 2-position 5. These products are
subjected to Suzuki coupling conditions with a diverse group of
aryl and heteroaryl boronic acids to afford analogs 6, and then N-
alkylated in order to generate the desired analogues 7. All final
products were purified using reverse-phase HPLC to >98% purity,
as determined by analytical LC/MS (215, 254 and ELSD). Overall
yields (5–57%) were good for the four step sequence.
The compounds generated were initially screened at a single
concentration of 3
dent signaling, against cell lines stably expressing either rat mGlu2
or rat mGlu3 and mouse G (Fig. 2). All assays were carried out
lM for their ability to alter glutamate-depen-
a
15
using a kinetic, plate-based, calcium-induced fluorescence reader,
using previously reported methods.21 From the initial group of
compounds, none appeared to potentiate glutamate-dependent
calcium signaling (EC20 of Glu) at either mGlu2 or mGlu3 when
Figure 2. Inhibition of mGlu2 response to an EC76 of glutamate and inhibition of
mGlu3 response to an EC87 of glutamate. Results are representative of three
independent experiments.
applied at 3 lM. Conversely, 6 of the 53 analogs 7 screened showed
robust inhibition of mGlu2, and 18 of the analogs 7 showed robust
inhibition of mGlu3, meaning they inhibited an ꢀEC80 glutamate
response by P50%. Thus, the initial library generated analogs
biased towards inhibition of mGlu3, based on the single point
screen. The most active compounds from this initial screen were
selected, and a concentration–response curve (CRC) was generated
for each one. These curves were generated using the cell lines and
agonist concentrations as in the single point assay, while using a
broad range of test-compound concentrations (30 lM–1 nM).
As has been previously reported with allosteric modulators for
mGlus, the SAR profile of these compounds was fairly steep, with
small structural changes leading to significant losses in effi-
cacy.21,25 When the R1 position was held constant as a phenyl ring,
O
O
b
OH
NH2
a
OH
NH
Br
O
Br
NH2
3
4
O
O
N
c
d
NH
NH
N
R2
N
R2
Br
N
N
N
N
R1
R1
R1
5
6
7
Scheme 1. Reagents and conditions: (a) NaNO2, HCl, SnCl2, À5 °C to rt, 2 h, 90%; (b) AcOH, NCCH2COR1 150 °C,
l
W, 5 min, 27–88%; (c) 10 mol % Pd(dppf)2Cl2, K3PO4, B(OH)2R2,
dioxane/H2O,130 °C, lW, 40 min, 34–95%; (d) LIHMDS, ICH3, THF, 50 °C, 2 h, 52–76%.

C. J. Wenthur et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2693–2698
2695
and R3 was held as a methyl, installation of a 3-sulfonylphenyl or
Table 1
3-pyridyl group at R2 yielded inhibitors with low-micromolar to
high nanomolar IC50s at both mGlu2 and mGlu3. In contrast, instal-
lation of a phenyl or 4-methoxyphenyl at this position yielded
compounds with very little effect. Truncation of this position to a
methyl group also resulted in much attenuated activity at both
receptors. Results from installation of 3-subsituted phenyl groups
at R1 are summarized in Table 1. In general, the presence of a 3-sul-
fonamidephenyl or 3-pyridyl at R2 again induces more robust inhi-
bition than their phenyl, 4-methoxyphenyl, or methyl
comparators. Some additional interesting trends can be seen by
comparing similar compounds across alterations at R1 exclusively.
When replacing the phenyl at R1 (as in 7a–7e) with a 3-fluoro phe-
nyl (as in 7f–7j), the analogous compounds generally exhibit a
reduction in potency at mGlu2 and mGlu3. In the case where a 3-
pyridyl is present at R2, this reduction is approximately 2-fold.
However, in the case where a 3-sulfonyl phenyl is at R2, the
potency reduction is even more pronounced: greater than 5-fold
at mGlu2, and greater than 10-fold at mGlu3. When a 3-methoxy-
phenyl is installed at R1 (7k–7o), the potencies of the resulting
compounds are similar to their phenyl analogues. An exception
to this trend is when a 3-pyridyl group is present at R2, as this com-
pound has notably diminished potency at the group II mGlu recep-
tors in relation to its phenyl comparator. For the analogues
screened here, having a 3-methylphenyl at R1 (7p–7r) results in
an overall decrease in potency. This decrease has a similar magni-
tude as was observed with 3-fluorophenyl at this position.
Structure and activities of analogs 7
O
N
N
R2
N
R1
7
R1
R2
IC50 mGlu2
(
lM)
IC50 mGlu3
(lM)
a
a
Entry
7a
1.93
0.884
SO 2NH2
7b
7c
>10
>10
(0)
(À4)
MeO
7d
7e
0.852
(17)
0.165
(59)
N
H3C
7f
7g
7h
7i
>10
(2)
>10
SO2NH2
F
F
F
F
F
(39)
(2)
MeO
N
(6)
Several 3-chlorophenyl (7s–7u) and 3-bromophenyl (7v–7x)
analogues were screened at R1 as well, allowing for analysis of
increasing size of halogens at this position. The general trend seen
is that potency decreases as halogen size increases, with 7u provid-
ing one notable exception. This compound has an increased
potency over its 3-fluoromethyl and phenyl comparators at mGlu2,
while its potency at mGlu3 is retained. The SAR data for 4-substi-
tuted phenyl groups at R1 is also summarized in Table 1. Those
compounds with phenyl, 4-methoxyphenyl, and methyl substitu-
tions at R2 are once again less active than their 3-sulfonamidephe-
nyl and 3-pyridyl analogues. The presence of a 4-fluorophenyl
group at R1 (7y–7ac) yielded compounds with retained or mod-
estly increased potencies at mGlu2 and mGlu3, as compared to
7a–7e. The exception to this is 7y, which has an approximately
2-fold decrease in potency. Notably, the presence of a 3-pyridyl
group at R2 resulted in the most potent compound generated from
this initial screen, 7ab, with an IC50 of 427 nM at mGlu2 and 67 nM
1.56
(16)
0.247
(38)
H3C
7j
7k
7l
1.39
>10
(6)
0.696
>10
SO2NH2
OMe
OMe
OMe
OMe
OMe
7m
7n
7o
(48)
1.18
>10
MeO
3.12
>10
N
at mGlu3. Placing
a
4-chlorophenyl group at R1 (7ad–7ah)
decreased the maximal inhibition achieved, as compared to 7a–
7e. These compounds appear to be partial antagonists with rela-
tively high affinity for the group II mGlus; their CRC’s reach a max-
H3C
imum of around 60% inhibition at 1 lM, and do not cause any
7p
7q
7r
(7)
(49)
(34)
0.53
further decrease in signal when applied at higher concentrations.
Finally, analogs 7 that contained a 4-methoxyphenyl, a 4-trifluoro-
methoxyphenyl, or a 4-ethylphenyl group at R1 resulted in com-
pounds with severely attenuated potency. Likewise, the presence
of multiply substituted phenyl rings at R1, specifically 3,4-difluoro-
phenyl and 3,5-dimethoxyphenyl groups, resulted in compounds
with little inhibitory activity at mGlu2 or mGlu3 (data not shown
in Table 1).
In a further attempt to expand the search for the molecular
basis of mode switching that had been reported with this series,
several analogues were made which examined alternative N-alkyl
groups (Table 2), following the synthetic scheme depicted in
Scheme 2. Starting from 8, an analog of 6, deprotonation with
LiHMDS and trapping with either 2-iodoethanol or acetyl chloride
afforded analogs 9. These compounds retained a phenyl group at
R1, and either a 3-pyridinyl or phenyl group at R2. The presence
of a hydrogen (8a, 8b) or acetyl group (9a, 9c) at R3 did not appear
(0)
MeO
N
1.79
7s
7t
(7)
(19)
Cl
Cl
Cl
(9)
(31)
MeO
N
7u
0.564
0.293
(continued on next page)

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C. J. Wenthur et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2693–2698
Given the trend seen with 7a–7ah, wherein the presence of a 3-
Table 1 (continued)
pyridyl group at R2 resulted in compounds with elevated potency
at mGlu2 and mGlu3, it was decided to explore the effects of addi-
tional heterocyclic replacements at R2 while retaining R1 as a phe-
nyl group (Table 3). As compared to 7d, the analogues with benzo-
fused heterocycles at R2 (10c–10g) all had significantly diminished
potency at mGlu2 and mGlu3. Installation of a 4-pyridyl group also
caused a relative decrease in potency. In contrast, when a 3,5-
pyrimidyl group is present at the R2 position, it increased potency
by nearly 3.5-fold at mGlu2 and by over 2-fold at mGlu3. The
resulting compound, 4-methyl-2-phenyl-8-(pyrimidin-5-yl)pyraz-
olo[1,5-a]quinazolin-5(4H)-one (10b), was the most potent inhibi-
tor of group II mGlus discovered from this scaffold, with an IC50 of
245 nM (pIC50 = 6.611 0.055) at mGlu2, and 78 nM
(pIC50 = 7.108 0.073) at mGlu3.
a
a
Entry
R1
R2
IC50 mGlu2
(lM)
IC50 mGlu3
(lM)
7v
(8)
(4)
>10
(28)
Br
Br
Br
7w
7x
(23)
MeO
N
>10
7y
3.95
1.99
F
SO2NH2
7z
(12)
>10
(64)
>10
Due to its potency, 10b was selected as an exemplar compound
from this series for further pharmacological characterization. In
order to determine its mechanism of action (competitive orthos-
teric antagonism or negative allosteric modulation), 10b was
screened at several fixed concentrations against mGlu2 and mGlu3
F
F
F
F
7aa
7ab
7ac
MeO
N
0.427
>10
0.067
>10
against an increasing concentration of glutamate (1 nM–30 lM). It
H3C
diminished the response to glutamate in a dose-dependent manner
at both mGlu2 and mGlu3, indicating that it is acting as a NAM,
rather than a competitive antagonist (Fig. 3).
7ad
0.847
1.25
Additionally, to measure the broader selectivity profile of this
compound, it was screened against the entire family of mGlu
Cl
SO2NH2
7ae
7af
(4)
(31)
(21)
0.645
(33)
Cl
Cl
Cl
Cl
(6)
O
N
O
N
MeO
R3
a
NH
N
7ag
7ah
1.11
(11)
N
R2
R2
H3C
N
N
a
8
9
Where IC50s were not determined, percent inhibition of EC76 (mGlu2) or EC87
(mGlu3) at 3 M is reported in parentheses. Results are representative of three
l
independent experiments.
Scheme 2. Reagents and conditions: (a) LiHMDS, electrophile, THF, 50 °C, 2–8 h,
30–54%.
Table 2
Structure and activities of analogs 8 and 9
Table 3
O
O
N
Structure and activities of analogs 10
R3
NH
N
O
N
R2
R2
N
N
N
R2
N
N
8
9
10
Entry
8a
R2
R3
IC50 mGlu2
(
l
M)a
IC50 mGlu3 (l
M)a
Entry
R2
IC50 mGlu2
1.77
(lM)
IC50 mGlu3
0.509
(lM)
a
a
H
(2)
(3)
(0)
(6)
(8)
(3)
O
10a
N
N
9a
OH
OH
10b
10c
10d
0.245
(9)
0.078
(34)
>10
9b
N
H
N
H
8b
9c
9d
(4)
(8)
N
H
N
O
>10
N
N
>10
4.65
>10
3.15
N
N
10e
10f
10g
(4)
>10
(0)
(33)
4.51
(16)
N
a
Where IC50s were not determined, percent inhibition of EC76 (mGlu2) or EC87
(mGlu3) at 3 M is reported in parentheses. Results are representative of three
independent experiments.
l
N
N
to be tolerated for these compounds, and installation of an ethanol
group resulted in a significant decrease in potency at mGlu2 and
mGlu3 (9b, 9d).
a
Where IC50s were not determined, percent inhibition of EC76 (mGlu2) or EC87
(mGlu3) at 3 M is reported in parentheses. Results are representative of three
independent experiments.
l

C. J. Wenthur et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2693–2698
2697
receptors at a fixed concentration of 10
lM. At this concentration
10b showed a 3-fold shift of mGlu1 and had completely blocked
the glutamate response at mGlu2 and mGlu3, but it did not alter
the responses of the other mGlus to glutamate (Fig. 4). These data
indicate that this scaffold can deliver compounds with highly pref-
erential activity at group II mGlus, in comparison to the group I and
group III receptors. Overall, these results indicate that potent dual
inhibitors of mGlu2 and mGlu3, such as 10b, are rapidly accessible
via alterations to a pyrazolo[1,5-a]quinazoline-5(4H)-one scaffold.
Based on the attractive mGlu selectivity profile and favorable
calculated properties (MW = 353, clogP = 2.72, tPSA = 60), we eval-
uated 10b in a tier 1 DMPK panel to assess its disposition profile.
Unfortunately, 10b was very highly bound to protein in both rat
(fu 0.003) and human (fu 0.008) plasma, and had a predicted clear-
ance near hepatic blood flow in rat and human (CLhep of 54.7 mL/
min/kg and 18.7 mL/min/kg, respectively). Compound 7ab exhib-
ited similarly poor DMPK properties. Due to the flat, aromatic char-
acter of 10b and 7ab, these results are understandable. Future
efforts in this series will employ metabolite identification studies
to identify soft spots, as well as increasing sp3 character in an
attempt to improve free fraction and lower clearance.
Notably, all of the compounds derived from this scaffold thus
far have been either equipotent at mGlu2 and mGlu3, or mGlu3-
preferring. Indeed, of the compounds in this series that had
P90% inhibition at mGlu2 and mGlu3, all of them were more
potent at mGlu3. It remains to be seen whether further exploration
Figure 4. Fold-shifts of mGlu signaling across the group I and group III receptors.
Group I signaling measured using calcium response, group III measured using GIRK
response. All responses measured at rat receptors, aside from mGlu1 and mGlu6,
which used human receptors.
of substitutions off of the quinazoline or pyrazole rings will yield
compounds with an increased preference for inhibition of mGlu3,
and whether the generation of selective mGlu2 NAMs or mGlu3
PAMs from this series requires more extensive alterations. Contin-
ued efforts to develop subtype selective tool compounds are
underway and will be reported in due course.
Acknowledgments
Thanks to Darren Engers and Corey Hopkins for their several
helpful discussions regarding analogue selection, to Meredith
Noetzel and Atin Lamsal for their assistance with the mGlu selec-
tivity panel, and to Caitlin Li for her synthetic support. This work
was supported by the NIH/MLPCN and Houses the Vanderbilt Spe-
cialized Chemistry Center for Accelerated Probe Development sup-
ported by U54 MH084659. The support of William K. Warren, Jr.
who funded the William K. Warren, Jr. Chair in Medicine (to
C.W.L.) is gratefully acknowledged.
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