Discovery and SAR of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of mGlu5

Article abstract of DOI:10.1016/j.bmcl.2009.10.024

A high-throughput cell-based screen identified a series of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of metabotropic glutamate receptor 5 (mGlu₅). This Letter describes the SAR of this series and the profile of selected

Full text of DOI:10.1016/j.bmcl.2009.10.024

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6623–6626
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and SAR of 6-substituted-4-anilinoquinazolines
as non-competitive antagonists of mGlu5
Andrew S. Felts a,c, Sam A. Saleh a,c, Uyen Le a,c, Alice L. Rodriguez a,c, C. David Weaver a,c, P. Jeffrey Conn a,c
,
Craig W. Lindsley a,b,c, Kyle A. Emmitte a,c,
*
a Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
b Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
c Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, 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:
A high-throughput cell-based screen identified a series of 6-substituted-4-anilinoquinazolines as non-
competitive antagonists of metabotropic glutamate receptor 5 (mGlu5). This Letter describes the SAR
of this series and the profile of selected compounds in selectivity and radioligand binding assays.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 14 August 2009
Revised 2 October 2009
Accepted 5 October 2009
Available online 9 October 2009
Keywords:
Glutamate
Metabotropic glutamate receptor 5
Negative allosteric modulator
Non-competitive antagonist
Quinazoline
Glutamate is the major excitatory transmitter in the mamma-
lian CNS, exerting its effects through both ionotropic and metabo-
tropic glutamate receptors. The metabotropic glutamate receptors
(mGlus) belong to family C of the G-protein-coupled receptors
(GPCRs). These receptors are characterized by a seven transmem-
from phase II clinical studies with two small molecule mGlu5
NAMs, ADX10059 in GERD9 and acute migraine10 and fenobam
(Fig. 1) in fragile X syndrome.11 With such a large body of compel-
ling evidence, the search for new and improved mGlu5 NAMs re-
mains an attractive and active area for drug discovery research.12
We have recently reported our initial results from an effort to
identify mGlu5 antagonists from multiple diverse chemotypes.13
A functional cell-based high-throughput screen of a collection of
160,000 compounds identified 624 mGlu5 antagonists. The confir-
mation of hits using full concentration response curves left 345
verified non-competitive antagonists of the target. Among that
set of confirmed hits were a few 6-bromo-4-anilinoquinazolines.
3-Chloroaniline analog 1 (Fig. 2) represented the most potent com-
pound in our functional assay, which measures the ability of the
compound to block the mobilization of calcium by an EC80 concen-
brane (7TM) a-helical domain that is connected via a cysteine-rich
region to a large bi-lobed extracellular amino-terminal domain.
The eight mGlus discovered to date have been further divided
according to their structure, preferred signal transduction mecha-
nisms, and pharmacology (Group I: mGlu1 and mGlu5; Group II:
mGlu2 and mGlu3; Group III: mGlu4, mGlu6, mGlu7, and mGlu8).1
Whereas orthosteric ligands of mGlus bind in the amino-termi-
nal domain of the receptor, known allosteric binding sites are lo-
cated in the 7TM domain. Orthosteric ligands often suffer from
poor selectivity among the mGlus due to a highly conserved bind-
ing site. The discovery of non-competitive antagonists, also known
as negative allosteric modulators (NAMs), has offered a potential
solution to such selectivity issues.2 The mGlu5 NAMs 2-methyl-6-
(phenylethynyl)pyridine (MPEP)3 and 3-[(2-methyl-1,3-thiazol-4-
yl)ethynyl]pyridine (MTEP)4 (Fig. 1) have demonstrated efficacy
in numerous preclinical models of disease, including pain,5 anxi-
ety,6 gastroesophageal reflux disease (GERD),7 and fragile X syn-
drome.8 In addition, there have been recent positive disclosures
tration of glutamate in HEK293A cells expressing rat mGlu5.14
A
binding affinity determination measuring the ability of the com-
* Corresponding author.
E-mail address: kyle.a.emmitte@Vanderbilt.edu (K.A. Emmitte).
Figure 1. mGlu5 NAMs MPEP, MTEP, and fenobam.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.024

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A. S. Felts et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6623–6626
ring appeared to improve potency as unsubstituted aniline 2 was
only weakly active. 3-Fluoroaniline 3 exhibited improved potency
relative to 2, while 3-bromoaniline 4 and 3-methylaniline 5 were
comparable in activity to the hit compound 1. The sensitivity of
this position to subtle modifications was evident as 3-trifluoro-
methylaniline 6 was sevenfold less potent than 5. 3-Methoxyani-
line 7 was only weakly active, similar to 2.
We also decided to examine various substituents at the 6-posi-
tion of the quinazoline ring while maintaining the 3-chloroaniline
substituent (Table 2). Other halogens at this position (8 and 9)
were similar in potency to the hit compound (1). 6-Nitroquinazo-
line 10 had comparable activity to the 6-halogen compounds. 6-
Methoxy (11) and 6-cyano (12) quinazolines were less potent.
Other substituents, including larger aryl and heteroaryl groups
(data not shown) were not tolerated and resulted in a complete
loss of activity.
Another area of interest was the quinazoline core of the tem-
plate. As such, we prepared a few modified cores (Table 3). 6-Chlo-
roquinoline analog 14 was essentially inactive in our assay, which
was a dramatic change from the potent antagonist activity ob-
served with comparator 6-chloroquinazoline 13. Modification of
the template to afford 7-bromoisoquinoline 15 reduced the activity
by approximately 25-fold relative to 6-bromoquinazoline compar-
ator 4. Such results further illustrate how small structural modifi-
cations within this chemotype can profoundly impact the observed
mGlu5 activity.
Figure 2. mGlu5 NAM quinazoline screening hit.
pound to compete with the equilibrium of [3H]3-methoxy-5-(pyri-
din-2-ylethynyl)pyridine,15 a close structural analog of MPEP, con-
firmed the interaction of 1 with the known allosteric binding site.16
The quinazoline scaffold as a chemotype for mGlu5 antagonists
has been disclosed by Grüenenthal GmbH in the patent literature
in the form of 6-aryl-4-aminoquinazolines.17 Quinazolines were
also used by Yamanouchi Pharmaceutical Company,18 Eli Lilly,19
and Pfizer20 to design mGlu1 antagonists. Nonetheless, an investi-
gation of the SAR of 6-substituted-4-anilinoquinazolines as non-
competitive antagonists of mGlu5 has yet to be disclosed. The
development of such SAR is the subject of this Letter.
Quinazoline derivatives of interest were readily accessible
through SNAr reaction of the appropriate nucleophiles with com-
mercially available 6-substituted-4-chloroquinazolines using
microwave-assisted organic synthesis (MAOS)22 (Scheme 1). Such
chemistry was amenable to our preferred iterative library synthe-
sis approach, which in combination with our custom mass-direc-
ted HPLC purification system allows for rapid evaluation of new
screening hits.23 Prior to biological testing, all compounds were
analyzed by LC–MS and determined to be P95% pure, and selected
compounds were further characterized by proton NMR.24 Initially,
we decided to conduct a small scan with commercially available 3-
substituted anilines while maintaining the 6-bromoquinazoline
functionality (Table 1). Substitution at the 3-position of the aniline
Table 2
SAR of 6-substituted quinazolines
% Glu maxb
a
Compound
R
mGlu5 IC50 (nM)
1
8
9
10
11
12
Br
F
Cl
NO2
OMe
CN
256 68
311 74
130 28
274 70
1510 365
>10,000c
1.5 0.3
0.9 0.2
2.8 0.4
2.4 0.6
13
7
35 11
Scheme 1. Reagents and conditions: (a) 3.0 equiv of Et3N, 1.0 equiv of R2-NH2 or
a
R2-NHMe, EtOH; (b) 1.2 equiv of K2CO3, 1.0 equiv of R2-SH or R2-OH, acetone.
Calcium mobilization mGlu5 assay; values are average of n P 3.
Amplitude of response in the presence of 30 lM test compound as a percentage
b
of maximal response (100
lM glutamate); average of n P 3.
c
CRC does not plateau.
Table 1
SAR of 3-substituted anilines
Table 3
Core modifications
% Glu maxb
a
Compound
R
mGlu5 IC50 (nM)
1
2
3
4
5
6
7
Cl
H
F
Br
Me
CF3
OMe
256 68
>10,000c
1970 235
174 26
246 48
1720 127
>10,000c
1.5 0.3
42 13
8.8 3.0
2.5 0.7
1.2 0.3
3.2 0.6
34 14
a
Compound
R
A1
A2
mGlu5 IC50 (nM)
% Glu maxb
13
14
4
Cl
Cl
Br
Br
N
N
N
CH
N
CH
N
124 29
>30,000
1.2 0.1
—
2.5 0.7
5.4 1.7
174 26
4330 1200
15
N
a
Calcium mobilization mGlu5 assay; values are average of n P 3.
Amplitude of response in the presence of 30
of maximal response (100
b
a
lM test compound as a percentage
Calcium mobilization mGlu5 assay; values are average of n P 3.
b
lM glutamate); average of n P 3.
Amplitude of response in the presence of 30
of maximal response (100
lM test compound as a percentage
M glutamate); average of n P 3.
c
CRC does not plateau.
l

A. S. Felts et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6623–6626
6625
Table 5
Linker modification SAR
We also explored the concept of extending the linker between
the 4-amine substituent and the aryl ring (Table 4). Both benzyl
amines (17–20) and phenethylamines (21–24) were investigated.
Only unsubstituted phenethylamine analog 21 exhibited any
antagonist activity, albeit weak. Chloro-substituted analogs failed
to demonstrate any improved activity, which was a significant con-
trast to the enhanced potency of 3-chloroaniline analog 9 relative
to unsubstituted analog 16.
% Glu maxb
a
Compound
R
X
mGlu5 IC50 (nM)
An additional area of interest was a survey of potential alterna-
tives to the secondary amine linker. Such work was accomplished
in the context of the 6-chloro and 6-bromoquinazolines (Table 5).
The N-methyl (25 and 28) and thiol (27 and 30) analogs proved
inactive in our assay. Only the ether analogs (26 and 29) demon-
strated weak antagonist activity. The consequences of the second-
ary amine (13 and 4) to ether (26 and 29) modifications were
severe, reducing potency by more than 50-fold in each case.
Once we concluded that secondary anilines were likely optimal
in this series, we sought to further evaluate the SAR around that
portion of the scaffold. One of the potential issues with this series
was the relatively high lipophilicity of the initial screening hit 1
(cLog P = 5.49).25 Having achieved a potent hit with 6-fluoroqui-
nazoline 8 (cLog P = 4.77), we decided to examine additional
substituted anilines in the context of this core (Table 6). As was
the case with the 6-bromoquinazolines, unsubstituted aniline 31
and 3-trifluoromethylaniline 34 were weak antagonists. 3-Bromo
aniline 32 was a potent antagonist, while 3-methyl aniline 33
was only moderately potent. The moderate potency of 33 repre-
sented a departure from the SAR observed with the 6-bromoqui-
nazolines, where 3-methylaniline 5, 3-chloroaniline 1, and 3-
bromoaniline 4 were essentially equipotent. The 3-cyanoaniline
35 was moderately potent, similar to 33. Interestingly, 3-ethylani-
line 36 was a weak potentiator, or positive allosteric modulator
13
25
26
27
4
28
29
30
Cl
Cl
Cl
Cl
Br
Br
Br
Br
NH
NMe
O
124 29
>30,000
1.2 0.1
—
6570 1010
>30,000
14
—
8
S
NH
NMe
O
174 26
>30,000
2.5 0.7
—
49 14
—
>10,000c
>30,000
S
a
Calcium mobilization mGlu5 assay; values are average of n P 3.
b
Amplitude of response in the presence of 30
l
M test compound as a percentage
lM glutamate); average of n P 3.
of maximal response (100
c
CRC does not plateau.
Table 6
Aniline SAR of 6-fluoroquinazolines
% Glu maxb
0.9 0.2
a
Compound
R
mGlu5 IC50 (nM)
8
31
32
33
34
35
36
37
38
39
40
41
3-Cl
H
3-Br
3-Me
3-CF3
3-CN
3-Et
311 74
(EC50 >10 lM; % Glu max = 52 5 in the presence of an EC20 con-
>10,000c
58
8
centration of glutamate). Such a switch in mGlu5 pharmacology
has been noted and reported before in our laboratory in the context
of other chemotypes.13,14 3-Methoxyaniline 37 was a weak antag-
onist. We also prepared a few analogs (38–41) in order to evaluate
the effect of fluoro substitution in the context of the 3-chloroani-
line. In every case, fluoro substitution proved detrimental to po-
tency. 2-Fluoro-3-chloroaniline 39 demonstrated moderate
potency, while other analogs were only weak antagonists.
96 12
0.6 0.2
3.5 0.8
32 16
1350 201
>10,000c
1370 198
Weak potentiator
>10,000c
3.5 0.6
3-OMe
3-Cl, 4-F
2-F, 3-Cl
3-Cl, 5-F
2-F, 5-Cl
50
6
>10,000c
34 17
5.2 1.4
3720 573
>10,000c
56
58
8
8
>10,000c
a
Calcium mobilization mGlu5 assay; values are average of n P 3.
b
Table 4
Amplitude of response in the presence of 30
lM test compound as a percentage
SAR of extended linkers
of maximal response (100
lM glutamate); average of n P 3.
c
CRC does not plateau.
Having identified some molecules with good potency in our
cell-based functional assay, we decided to further profile these
analogs with regard to binding affinity and selectivity (Table 7).
Data for MPEP is shown as a comparator. Binding affinity determi-
nations with [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine con-
firmed the interaction of 13 and 32 with the known MPEP
allosteric binding site, as was the case with hit compound 1. The
same three compounds were also examined for their selectivity
versus additional mGlus and were determined to be inactive
against mGlu2–4 and mGlu7–8. On the other hand, each compound
demonstrated moderate antagonist activity of mGlu1 in a calcium
mobilization assay.26 Recent publications indicate possible links
between mGlu1 and anxiety6a,27 as well as pain28 and fragile X.29
Such an overlap with regard to therapeutic applications makes
the concept of dual antagonism of mGlu1 and mGlu5 potentially
interesting.
% Glu maxb
a
Compound
R
n
mGlu5 IC50 (nM)
16
9
H
3-Cl
H
4-Cl
3-Cl
2-Cl
H
4-Cl
3-Cl
2-Cl
0
0
1
1
1
1
2
2
2
2
>10,000c
130 28
>30,000
>30,000
>30,000
>30,000
>10,000c
>30,000
>30,000
>30,000
31 12
2.8 0.4
—
—
—
—
17
18
19
20
21
22
23
24
59
—
3
—
—
a
Calcium mobilization mGlu5 assay; values are average of n P 3.
b
Amplitude of response in the presence of 30
l
M test compound as a percentage
It is worth commenting on the fact that 4-anilinoquinazolines
are well established as an effective template for the design of
of maximal response (100
lM glutamate); average of n P 3.
c
CRC does not plateau.

6626
A. S. Felts et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6623–6626
10. Goadsby, P. J.; Keywood, C. G. Abstracts of Papers, 61st Annual Meeting of the
Table 7
American Academy of Neurology, Seattle, WA, April 25ÀMay 2, 2009;
Binding affinity and selectivity of selected compounds
American Academy of Neurology: Saint Paul, MN; P06.006.
a
a
Compound
mGlu5 IC50 (nM)
mGlu5 Kib (nM)
mGlu1 IC50 (nM)
11. Berry-Kravis, E. M.; Hessl, D.; Coffey, S.; Hervey, C.; Schneider, A.; Yuhas, J.;
Hutchinson, J.; Snape, M.; Tranfaglia, M.; Nguyen, D. V.; Hagerman, R. J. Med.
Genet. 2009. doi:10.1136/jmg.2008.063701.
12. (a) Lindsley, C. W.; Emmitte, K. A. Curr. Opin. Drug Discovery Dev. 2009, 12, 446;
(b) Gasparini, F.; Bilbe, G.; Gomez-Mancilla, B.; Spooren, W. Curr. Opin. Drug
Discovery Dev. 2008, 11, 655; (c) Jaeschke, G.; Wettstein, J. G.; Nordquist, R. E.;
Spooren, W. Expert Opin. Ther. Pat. 2008, 18, 123.
13. Rodriguez, A. L.; Williams, R.; Zhou, Y.; Lindsley, S. R.; Le, U.; Grier, M. D.;
Weaver, C. D.; Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett. 2009, 3209.
14. HEK293A cells expressing rat mGluR5 or BHK cells expressing rat mGluR1
were cultured and plated as previously described. The cells were loaded with a
Ca2+-sensitive fluorescent dye and the plates were washed and placed in the
Functional Drug Screening System (Hamamatsu). Test compound was applied
to cells 3 s after baseline readings were taken. Cells were incubated with the
test compounds for 140 s and then stimulated with an EC20 concentration of
glutamate; 60 s later an EC80 concentration of agonist was added and readings
taken for an additional 40 s. Allosteric modulation by the compounds was
measured by comparing the amplitude of the responses at the time of
MPEP
1
13
3.5 1.4
256 68
124 29
96 12
4.7 1.5
116
249
—
398 33
955 115
713 102
32
736
a
Calcium mobilization assays; values are average of n P 3.
Ki values are average of n = 2.
b
inhibitors of epidermal growth factor receptor (EGFR) and other
members of the ErbB kinase family.30 In fact, dichloro analog 9
has been reported to moderately inhibit EGFR autophosphorylation
(IC50 = 2.7 l
M) in A431 cells.31 While this level of potency is mark-
edly less than that observed toward mGlu5 in our functional cell-
based assay, monitoring potential off-target activity against such
kinases will be necessary in the further development of this series
as mGlu5 non-competitive antagonists.
In summary, we have identified a series of non-competitive
antagonists of mGlu5 within the 6-substituted-4-anilinoquinazo-
line chemotype. Although the series was chemically unrelated to
MPEP, selected potent compounds were confirmed to inhibit bind-
ing of a radioligand at the MPEP allosteric binding site. While the
SAR in this series was somewhat shallow, several compounds dem-
onstrated moderate to good potency. Of further interest was the
dual activity of this series with respect to mGlu1.
glutamate addition plus and minus test compound. For
a more detailed
description of the assay, see: Sharma, S.; Rodriguez, A. L.; Conn, P. J.; Lindsley,
C. W. Bioorg. Med. Chem. Lett. 2008, 18, 4098.
15. Cosford, N. D. P.; Roppe, J.; Tehrani, L.; Schweiger, E. J.; Seiders, T. J.; Chaudary,
A.; Rao, S.; Varney, M. A. Bioorg. Med. Chem. Lett. 2003, 13, 351.
16. For a detailed description of the radioligand binding assay see Ref. 14.
17. Reich, M.; Oberbörsch, S.; Kühnert, S.; Haurand, M.; Schiene, K. WO 2007/
104560 A1, 2007.
18. Itahana, H.; Uekubo, T.; Nozawa, S.; Kako, H.; Okada, S.; Totani, A. JP
2003012653 A, 2003.
19. (a) Ambler, S. J.; Baker, S. R.; Clark, B. P.; Coleman, D. S.; Foglesong, R. J.;
Goldsworthy, J.; Jagdmann, G. E., Jr.; Johnson, K. W.; Kingston, A. E.; Owton, W.
M.; Schoepp, D. D.; Hong, J. E.; Schkeryantz, J. M.; VanNieuwenhze, M. S.; Zia-
Ebrahimi, M. S. WO 01/32632 A2, 2001.; (b) Shannon, H. E.; Peters, S. C.;
Kingston, A. E. Neuropharmacology 2005, 49, 188.
20. Mantell, S. J.; Gibson, K. R.; Osborne, S. A.; Maw, G. N.; Rees, H.; Dodd, P. G.;
Greener, B.; Harbottle, G. W.; Million, W. A.; Poinsard, C.; England, S.; Carnell,
P.; Betts, A. M.; Monhemius, R.; Prime, R. L. Bioorg. Med. Chem. Lett. 2009, 19,
2190.
Acknowledgments
22. Shipe, W. D.; Wolkenberg, S. E.; Lindsley, C. W. Drug Discovery Today: Technol.
2005, 2, 155.
23. Lindsley, C. W.; Weaver, D.; Jones, C.; Marnett, L.; Conn, P. J. ACS Chem. Biol.
2007, 2, 17.
The authors thank NIDA (RO1 DA023947-01) and Seaside Ther-
apeutics (VUMC33842) for their support of our programs in the
development of non-competitive antagonist of mGlu5. Matt Mul-
der, Chris Denicola, and Sichen Chang are also thanked for the puri-
fication of compounds using the mass-directed HPLC system.
24. For
a large scale synthesis, compounds can also be purified via flash
chromatography on silica gel. For example, synthesis and characterization of
1 was conducted as follows: 6-bromo-4-chloroquinazoline (1.0 g, 4.1 mmol),
3-chloroaniline (0.524 g, 4.1 mmol), triethylamine (1.25 g, 12.4 mmol) and
ethanol (10 mL) were added to a microwave vial and heated at 140 °C for
15 min. The ethanol was removed under reduced pressure and the crude
residue was dissolved in EtOAc and washed with aq NH4Cl (1Â), H2O (1Â),
brine (1Â). The organic layer was dried (MgSO4), filtered, and concentrated in
vacuo. Purification by flash chromatography on silica gel afforded 1.15 g (84%)
of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) d
9.93 (s, 1H), 8.86 (d, J = 1.9 Hz, 1H), 8.68 (s, 1H), 8.11 (t, J = 1.8 Hz, 1H), 8.00 (dd,
J = 8.9, 2.0 Hz, 1H), 7.84 (dd, J = 8.2, 1.1 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.42 (t,
J = 8.1 Hz, 1H), 7.18 (dd, J = 7.9, 1.2 Hz, 1H); ES-MS [M+1]+: 334.0.
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