Synthesis and SAR of novel, non-MPEP chemotype mGluR5 NAMs identified by functional HTS

Article abstract of DOI:10.1016/j.bmcl.2009.10.059

This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype identified by a functional HTS approach. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and further examples of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold.

Full text of DOI:10.1016/j.bmcl.2009.10.059

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6502–6506
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of novel, non-MPEP chemotype mGluR5 NAMs identified
by functional HTS
Ya Zhou a,c, , Alice L. Rodriguez a,c, , Richard Williams a,c, C. David Weaver a,c, P. Jeffrey Conn a,c
,
Craig W. Lindsley a,b,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, 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:
This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/
negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype identi-
fied by a functional HTS approach. This work demonstrates fundamentally new mGluR5 NAM chemo-
types with submicromolar potencies, and further examples of a mode of pharmacology ‘switch’ to
provide PAMs with a non-MPEP scaffold.
Received 21 July 2009
Revised 12 October 2009
Accepted 14 October 2009
Available online 28 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
mGluR5
Negative allosteric modulator
Positive allosteric modulator
Metabotropic glutamate receptors (mGluRs) are members of
the G protein-coupled receptor (GPCR) family C, which is distin-
guished from other GPCR families by its large extracellular N-ter-
minal agonist binding site. There are eight subtypes of mGluRs
(Group I: mGluR1 and mGluR5; Group II: mGluR2 and mGluR3;
Group III: mGluRs 4, 6, 7, 8) based on their sequence homology,
pharmacology and coupling to effector mechanisms.1 The mGluRs
bind glutamate to modulate neurotransmitter release or postsyn-
aptic excitatory neurotransmission, hence they modulate the
strength of synaptic transmissions. Different from ionotropic gluta-
mate receptors which mediate the fast excitatory neurotransmis-
sions, metabotropic glutamate receptors play a more modulatory
role and have been proposed as alternative targets for pharmaco-
logical interventions.1
thiopyrimidine (3) and fenobam (4), have been disclosed.12,13 Re-
cently our group reported three novel non-MPEP chemotypes of
mGluR5 antagonists (5, 6, and 7), which exemplified a dramatic
departure from the MPEP scaffold.14
As a continuing effort to design and synthesize novel non-
MPEP-based mGluR5 negative allosteric modulators (NAMs), in
this Letter, we describe the discovery and SAR of three novel
mGluR5 NAM series represented by 8, 9 and 10 (Fig. 2). These novel
leads were identified from a functional high-throughput mGluR5
Group I receptor mGluR5 has been implicated in a number of
physiological processesin thecentralnervous system(CNS). Thedis-
covery of highly selective mGluR5 receptor antagonists MPEP (1)
and MTEP (2) was a major breakthrough (Fig. 1). MPEP (1) and MTEP
(2) in preclinical models demonstrated that selective antagonism of
mGluR5 has therapeutic potential for the treatment of pain, anxiety,
depression, cocaine addiction and Fragile X Syndrome (FXS).2
A majority of reported non-competitive mGluR5 antagonists
have employed the MPEP (1) and MTEP(2) chemotypes as a basis
for ligand design.3–11 Only a few more diverse structures, such as
* Corresponding author. Tel.: +1 615 322 8700; fax: +1 615 343 6532.
E-mail address: carig.lindsley@vanderbilt.edu (C.W. Lindsley).
These authors contributed equally to this work.
Figure 1. Reported mGluR5 non-competitive antagonists/negative allosteric mod-
ulators (NAMs).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.059

Y. Zhou et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6502–6506
6503
Figure 2. Novel non-MPEP mGluR5 non-competitive antagonists 8, 9 and 10 identified from a functional HTS campaign.
Table 1
antagonist screen of over 160,000 compounds (624 mGluR5 antag-
onists identified, 0.39% hit rate in the primary screen).14 Leads 8, 9
and 10 all possess submicromolar IC50s from the HTS DMSO stock
solutions, good clogP values and low molecular weights, which are
ideal properties for further SAR development.
Structures and activities of analogs 14
Lead 8, an N,N’-(1,3-phenylene)dibenzamide, was first investi-
gated and SAR exploredthrough the synthesisof two small 24-mem-
bered libraries.15 The first library aimed at holding the
2-methoxybenzamide moiety constant, while varying the other
amide portion of the molecule. As illustrated in Scheme 1, synthesis
of key intermediate 13 was achieved by coupling of 3-nitroaniline 11
and 2-methoxybenzoyl chloride under mild basic conditions to pro-
vide 12, followed by hydrogenation with Raney nickel to deliver 13.
We applied an iterative parallel synthesis strategy for this library
preparation, as well as all the other libraries in this letter, and resyn-
thesized 8 in the context of a 24-member library through standard
acylation of 13 with 24 commercial acid chlorides. Excess reagents
were scavenged by PS-isocyanate and PS-trisamine, and the final
products were purified by mass-directed preparative LC–MS to
>98% purity.16
Compd
R
mGluR5a IC50
0.88
(lM)
% Glu max
8
2.6
ND
14a
14b
14c
>30
>30
>30
ND
ND
Upon resynthesis, lead 8 suffered a threefold loss in potency
(IC50 = 880 nM) compared to the HTS stock solution (IC50 = 301 nM);
however, clearSAR wasstill notedfor thisseries (Table 1). Lead 8 was
the most potent compound. Aromatic groups were the only active
analogs; meta-substitution was favored (14e, 14g, 14h and 14i,
potency Cl > Me > CN > F > CF3), any other substitution patterns in
the aromatic ring were not tolerated (14a–14d, 14f and 14j). Intro-
ductionofothergroups, suchasheterocyclicderivative(14k), benzyl
variant (14l), cyclic alkyl moieties (14n–14r), or acyclic alkyl deriv-
atives (14s–14u), were all proven inactive.
A second library was prepared in similar fashion with the goal
of holding the 3-chloro group constant, while changing the other
amide moiety. As shown in Scheme 2, synthesis of key intermedi-
ate 16 was achieved by coupling of 3-nitroaniline 11 and 3-chor-
obenzoyl chloride under mild basic conditions to provide 15. A
subsequent Raney nickel-catalyzed hydrogenation at atmospheric
pressure delivers 16. A 24-member library 17 was synthesized
through standard acylation of 16 with 24 readily available acid
chlorides.14 Excess reagents were scavenged by PS-isocyanate
14d
>30
ND
14e
14f
6.48
>30
25.8
ND
14g
14h
14i
10.60
1.80
1.35
26.1
3.22
3.82
14j
14k
14l
>30
>30
>30
ND
ND
ND
14m
14n
>30
>30
ND
ND
Scheme 1. Reagents and conditions: (a) 2-methoxybenzoyl chloride, DIEA, DMAP,
DMF, 64%; (b) Raney nickel, H2 (50 psi), EtOH/EtOAc (3:2), 94%; (c) (i) RCOCl, PS-
DMAP, PS-DIEA; (ii)PS-isocyanate, PS-trisamine, 25–90%.
14o
>30
ND
(continued on next page)

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Y. Zhou et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6502–6506
Table 2
Table 1 (continued)
Structures and activities of analogs 17
Compd
R
mGluR5a IC50
>30
(l
M)
% Glu max
ND
14p
14q
14r
>30
>30
ND
ND
Compd
R
mGluR5a IC50
(l
M)
% Glu max
8.78
17a
2.62
14s
>30
ND
14t
>30
>30
ND
ND
17b
>30
ND
14u
a
IC50s are average of three determinations. ND not determined.
17c
17d
17e
17f
17g
17h
17i
>30
>30
>30
>30
>30
>30
>30
ND
ND
ND
ND
ND
ND
ND
and PS-trisamine, and the final products were purified by mass-di-
rected preparative LCMS with purity >98%.16
Generally (Table 2), aromatic groups were not well tolerated
(17b–17i), with exception of the 2-chlorophenyl analog 17a
(IC50 = 2.62 lM) which proved to be the most potent NAM in this
series, along with the cylcopropyl amide 17q. Benzyl analog 17k,
phenylcyclopropane derivative 17l and adamantyl compound
17m proved inactive. Interestingly, 6- and 5-member cyclic alkyl
moieties were inactive (17n and 17o). However, a cyclobutyl
amide provided a NAM of modest potency (17p, IC50 = 5.27
and further contraction to the cyclopropyl derivative 17q led to im-
proved inhibition (IC50 = 2.23 M). Acyclic alkyl analogs 17r and
lM),
l
17s both demonstrated weak inhibition, while the ether variant
17t showed no activity. Most surprising from this library (Fig. 3)
was the identification of two weak, but unexpected mGluR5 posi-
tive allosteric modulators (PAMs) 17u (EC50 = 1.87
lM, 49% Glu
Max) and 17v (EC50 = 5.54
lM, 56% Glu Max), both regiosiomeric
pyridine amide analogs.14,17,18 While weak, 17u and 17v represent
a fundamentally new mGluR5 PAM chemotype, worthy of further
optimization.17–22
17j
4.51
>30
49.3
ND
From this N,N’-(1,3-phenylene)dibenzamide series, 8 was fur-
ther evaluated and found to displace [3H]3-methoxy-5-(2-pyridin-
ylethynyl) pyridine, a radioligand for the MPEP allosteric binding
17k
site on mGluR5, with a Ki value of 1.1 lM, comparable to the IC50
17l
>30
ND
value (880 nM). Thus 8 represents a new mGluR5 non-competitive
antagonist chemotype, inhibiting mGluR5 function by interaction
with MPEP allosteric binding site. Future libraries will focus on
SAR studies of the central phenyl core modifications.
Our attention was then directed to lead 9, 3-(phthalimidyl)-N-
(2-hydroxyphenyl)benzamide. Lead 9 possesses very similar struc-
ture to CPPHA,20,21 the only known mGluR5 allosteric ligand, a
PAM, that binds at an allosteric site distinct from the MPEP-binding
17m
17n
>30
>30
ND
ND
17o
17p
>30
ND
44
5.27
17q
17r
2.23
5.82
32.3
26.9
17s
17t
7.97
>30
39.6
ND
Scheme 2. Reagents and conditions: (a) 3-chlorobenzoyl chloride, DIEA, DMAP,
DMF, 89%; (b) Raney nickel, H2 (1.0 atm), EtOH/EtOAc (3:2), 89%; (c) (i) RCOCl, PS-
DMAP, PS-DIEA; (ii)PS-isocyanate, PS-trisamine, 28–92%.
a
IC50s are average of three determinations.ND not determined.

Y. Zhou et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6502–6506
6505
Table 3
site (Fig. 4). We resynthesized 9 in the context of a 22-member
Structures and activities of analog 22
library. Preparation of the library was straightforward as indicated
in Scheme 3. Condensation between readily available methyl
3-aminobenzoate 18 and phthalic anhydride 19 in acetic acid affor-
ded methyl 3-(N-phthalimidyl)benzoate 20. Saponification of 20
using lithium hydroxide gave benzoic acid 21. Scaffold 21 was then
coupled to 22 different amines employing HOBt/EDC, to deliver the
3-(N-phthalimidyl) benzamide library 22. The final products were
purified by mass-directed preparative LC–MS to >98% purity.16
Upon resynthesis, lead 9 suffered a fivefold loss in potency
(IC50 = 417 nM) compared to the HTS stock solution (IC50 = 77 nM)
(Table 3). The discrepancies between the resynthesized com-
pounds and HTS DMSO stocks have been noted many times in
our various programs previously.14,17 Lead 9 was still the most
potent compound in this series. In general, functionalized aromatic
and heteroaromatic analogs were more active (9, 22a–22h), and
Compd
R
mGluR5a IC50
(l
M)
% Glu max
9
0.42
1.59
48.1
22a
22b
7.79
3.58
alkyl derivatives were inactive (22i, 22j, IC50 >30
the hydroxyl group of 9 from the 2-position to 3-position (22a),
led to a 19-fold loss in potency (IC50 = 7.79 M). 3,5-Dimethoxyl
inhibitory activity
M), while 2-methoxyl analog 22c lost all the activity.
lM). Moving
l
substrate
22b
showed
moderate
76.2
86
(IC50 = 3.58
l
22c
>30
22d
22e
22f
1.78
>30
26.4
86
Figure 3. Novel non-MPEP mGluR5 PAMs 17u and 17v.
1.26
59.5
22g
22h
1.05
>30
49.9
73
Figure 4. Structural similarity of 9 and non-MPEP-binding mGluR5 PAM, CPPHA.
22i
22j
>30
>30
68
71
a
IC50s are average of three determinations.
3-Chloro
derivative
22d
displayed
improved
potency
(IC50 = 1.78
lM) compared to 3-hydroxyl analog 22a. 3-Pyridyl
compound 22e proved inactive, however, its 2-pyridyl congener
22f showed reasonable activity (IC50 = 1.26 M) as a partial antag-
onist.23 2-Flouro derivative 22g was favored over 4-flouro analog
22h, giving good potency (IC50 = 1.05 M) as a partial antagonist
as well.24 Considering the structural similarity of this series with
l
Scheme 3. Reagents and conditions: (a) HOAc, 100 °C, overnight, 100%, (b) LiOH,
THF/MeOH/H2O (4:1:1), 91%, (c) HOBt, EDC, DIEA, DMF, 35–90%.
l
Figure 5. Non-MPEP chemotype NAMs 23 and 25 as well as PAM 24, a non-MPEP site ligand, from a library of analogs of 10.

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Y. Zhou et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6502–6506
the non-MPEP-binding PAM CPPHA,20,21 we were hoping that this
series would also interact with this distinct allosteric binding site
and provide the first NAM tools to study the CPPHA binding site.
However, further evaluation of 9 showed the displacement of
2. (a) Gasparini, F.; Lingenhohl, K.; Stoehr, N.; Flor, P. J.; Heinrich, M.; Vranesic, I.
Neuropharmacology 1999, 38, 1493; (b) Lea, P. M., IV; Faden, A. I. CNS Drug Rev.
2006, 12(2), 149.
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Tamagnan, G. D. Bioorg. Med. Chem. Lett. 2005, 15, 945.
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a Ki of
4. Roppe, J. R.; Wang, B.; Huang, D.; Tehrani, L.; Kamenecka, T.; Schweiger, E. J.;
Anderson, J. J.; Brodkin, J.; Jiang, X.; Cramer, M.; Chung, J.; Reyes-Manalo, G.;
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A.; Gatti, S.; Mutel, V.; Malherbe, P. J. Pharmacol. Exp. Ther. 2005, 315, 711.
14. (a) 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, 19, 3209;
(b) mGluR5 in vitro functional assay. HEK293A cells expressing rat mGluR5
319 nM—a value comparable to the IC50 (420 nM), which indicated
its interaction with MPEP-binding site. Our continuing efforts will
focus on modifications of both the phthalimide moiety and the
central phenyl ring of the scaffold.
Lastly, our attention was directed at lead optimization of 10, N-
(3-(1H-benzo[d]imidazol-2-yl)-4-chlorophenyl)-5-bromofuran-2-
carboxamide. Once again, we resynthesized 10 in the context of a
small library of analogs.15 Surprisingly, upon resynthesis, lead 10
was totally inactive (IC50 >30
lM) and the majority of analogs dis-
played only poor activity at best (IC50s 10–30
l
M). This effort pro-
duced three interesting compounds (Fig. 5) 23 wherein the
chlorine of the central phenyl ring was replaced with hydrogen,
24 and 25 where the benzimidazole is replaced with a benzoxaz-
ole. In these examples, 23 was a weak mGluR5 NAM (IC50 = 3.5
34% Glu Max), 25 was a full mGluR5 NAM (IC50 = 2.1 M, 2.3% Glu
Max) while 24 was a modestly potent mGluR5 PAM (EC50 = 2.2 M,
lM,
l
l
68% Glu Max)—a very interesting ‘switch’ in the mode of mGluR5
pharmacology.17,18 Unlike 8 and 9, which afforded comparable
IC50s/Kis, 24 displaced [3H]3-methoxy-5-(2-pyridinylethynyl)pyri-
dine with a Ki >10-fold less than the EC50. These data are consistent
with the hypothesis that the PAM activity of 24 is mediated by
interaction with the MPEP site.25,26 Previous studies suggest that
mGluR5 PAMs acting at this site display strong cooperativity with
orthosteric agonists so that the mGluR5 PAM potencies are signif-
icantly greater than their affinities. However, based on these data,
it is also possible that 24 does not act solely through interaction
with the MPEP site, but potentially at the CPPHA site or a poten-
tially third allosteric site on mGluR5. Studies are underway to ad-
dress this question. Importantly, 8, 9, 23, 24 and 25 were selective
versus mGluRs 1, 2, 3, 4, 7 and 8.
In summary, our HTS campaign identified several novel non-
competitive mGluR5 antagonists based on 8 and 9 with little or
no structural and topological similarity to MPEP. An iterative par-
allel library synthesis strategy helped to rapidly develop SAR for
these series. IC50s of analogs of 8 and 9 ranged from 420 nM to
880 nM for the most potent mGluR5 NAMs and, despite divergence
from the MPEP chemotype, binding experiments indicated these
NAMs bound to the MPEP site. Optimization efforts also identified
fundamentally new mGluR5 PAM chemotypes, represented by 17u
and 17v, as well as new mGluR5 partial antagonists 22f and 22g.
While lead 10 was inactive upon resynthesis, both NAMs 23 and
25 and PAM 24 were identified within an analog library, and
PAM 24 displayed only weak displacement of [3H]3-methoxy-5-
(2-pyridinylethynyl) pyridine, suggesting 24 may not act solely
through interaction with the MPEP site. These data further high-
light the complexities and subtle modifications that can alter
modes of mGluR5 pharmacology for MPEP site ligands. Further
refinements in this arena are in progress and will be reported in
due course.
receptor were plated (BD Falcon Poly-D-lysine Cellware) at 50,000 cells/well in
assay media (DMEM, 20 mM HEPES, 10% dialyzed FBS, and 1 mM sodium
pyruvate). The plates were incubated overnight at 37 °C in 5% CO2. Media was
removed and assay buffer (Hanks Balanced Salt Solution, 20 mM HEPES,
2.5 mM Probenecid, pH 7.4) containing 4.0
added. Cells were incubated for 45 min (37 °C, 5% CO2) to allow for dye loading.
Dye was removed, 20 L assay buffer was added and the cell plate was allowed
lM Fluo4-AM dye (Invitrogen) was
l
to incubate for 10 min. After incubation in assay buffer, cell plates were loaded
into Flexstation II (Molecular Devices Corp). Test compound in assay buffer was
added 19 seconds into the assay and subsequently, asubmaximal (250 nM) or
nearly maximal (1.25
for potentiators and antagonists, respectively. Controls included compound
vehicle (0.2% DMSO) plus assay buffer, ECmax (100 glutamate), and
submaximal or nearly maximal concentrations of glutamate. Compounds
were tested in concentrations ranging from 46 pM to 100 M. Fold shifts were
determined using the same functional assay by varying the amount of
glutamate in the presence of either fixed concentration of compound
(10 M) or vehicle. concentration response curve was generated using
glutamate concentrations ranging from 4.6 nM to 10 M. Controls included
compound vehicle (0.2% DMSO) plus assay buffer, ECmax (100 V glutamate),
lM) amount of glutamate was added 109 s into the assay
l
V
l
a
l
A
l
l
and glutamate concentration response curve. Assays were performed in
triplicate on three different days. Concentration response curves were
generated using GraphPad Prism 4.0.
15. Kennedy, J. P.; Williams, L.; Bridges, T. M.; Daniels, R. N.; Weaver, D.; Lindsley,
C. J. Comb. Chem. 2008, 10, 345.
16. Leister, W. H.; Strauss, K. A.; Wisnoski, D. D.; Zhao, Z.; Lindsley, C. W. J. Comb.
Chem. 2003, 5, 322.
17. Sharma, S.; Rodriguez, A.; Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett.
2008, 18, 4098.
18. Sharma, S.; Heiman, J. U.; Rook, J. M.; Jones, C. K.; Conn, P. J.; Lindsley, C. W. J.
Med. Chem. 2009, 52, 4103.
19. O’Brien, J. A.; Lemaire, W.; Chen, T.-B.; Chang, R. S. L.; Jacobson, M. A.; Ha, S. N.;
Lindsley, C. W.; Sur, C.; Pettibone, D. J.; Conn, J.; Wiliams, D. L. Mol. Pharmacol.
2003, 64(3), 731.
20. O’Brien, J. A.; Lemaire, W.; Wittmann, M.; Jacobson, M. A.; Ha, S. N.; Wisnoski,
D. D.; Lindsley, C. W.; Schaffhauser, H. J.; Sur, C.; Duggan, M. E.; Pettibone, D. J.;
Conn, J.; Williams, D. L. J. Pharmacol. Exp. Ther. 2004, 309(2), 568.
21. Zhao, Z.; Wisnoski, D. D.; O’Brien, J. A.; Lemiare, W.; Williams, D. L., Jr.;
Jacobson, M. A.; Wittman, M.; Ha, S.; Schaffhauser, H.; Sur, C.; Pettibone, D. J.;
Duggan, M. E.; Conn, P. J.; Hartman, G. D.; Lindsley, C. W. Bioorg. Med. Chem.
Lett. 2007, 17, 1386.
22. Lindsley, C. W.; Wisnoski, D. D.; Leister, W. H.; O’Brien, J. A.; Lemiare, W.;
Williams, D. L., Jr.; Burno, M.; Sur, C.; Kinney, G. G.; Pettibone, D. J.; Tiller, P. R.;
Smith, S.; Duggan, M. E.; Hartman, G. D.; Conn, P. J.; Huff, J. R. J. Med. Chem.
2004, 47, 5825.
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4, 505.
Acknowledgments
The authors thank NIDA (DA023947-01) and Seaside Therapeu-
tics (VUMC33842) for support of our programs in the development
of mGluR5 non-competitive antagonists and partial antagonists.
24. Rodriguez, A. L.; Nong, Yi.; Sekaran, N. K.; Alagille, D.; Tamagnan, G. D.; Conn, P.
J. Mol. Pharmacol. 2005, 68, 793.
References and notes
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