Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

Article abstract of DOI:10.1016/j.bmcl.2011.01.044

This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu₅ receptor. 'Molecular switches' were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical model that shows similar positive effects with known antipsychotic agents.

Full text of DOI:10.1016/j.bmcl.2011.01.044

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1350–1353
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of centrally active mGlu5 positive allosteric modulators
based on an aryl acetylenic bicyclic lactam scaffold
Richard Williams a,c, Jason T. Manka a,c, Alice L. Rodriguez a,c, Paige N. Vinson a,c, Colleen M. Niswender a,c
,
C. David Weaver a,c, Carrie K. Jones a,c, P. Jeffrey Conn a,c, Craig W. Lindsley a,b,c, Shaun R. Stauffer a,b,c,
⇑
a Department of Pharmacology, Vanderbilt 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 hit-to-lead progression and SAR of a series of biphenyl acetylene compounds
derived from an HTS screening campaign targeting the mGlu5 receptor. ‘Molecular switches’ were iden-
tified that modulated modes of pharmacology, and several compounds within this series were shown to
be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical
model that shows similar positive effects with known antipsychotic agents.
Received 26 November 2010
Revised 11 January 2011
Accepted 12 January 2011
Available online 18 January 2011
Published by Elsevier Ltd.
Keywords:
mGluR
Potentiator
Positive allosteric modulator
Schizophrenia
Hyperlocomotion
The NMDA receptor hypofunction hypothesis is generally the
favored pathophysiological model for the disease mechanism for
schizophrenia.1,2 As a result, multiple approaches to enhance the
glutamate/NMDA system continue to be pursued as a means to
ameliorate the major symptom dimensions of the disease.1,2 Devel-
opment of positive allosteric modulators (PAMs) of the group I
metabotropic glutamate receptor mGlu5 continue to offer promise
as one such approach.3–6 After nearly a decade since the identifica-
tion of the first mGlu5 PAMs DFB (1),7 CPPHA (2),8,9 and CDPPB
(3),10,11 several chemically distinct series have recently emerged
including ADX47273 (4),12–14 a series of MPEP-based pyrimidines
(5)15,16 and nicotinamide (6),17,18 alkoxy biphenyl amides (7)19
and a chemically distinct series of piperazines (8).20,21 These second
generation PAMs offer several physiochemical advantages (e.g., sol-
ubility, unbound free fraction in biological relevant matrices) over
the first generation PAMs (Fig. 1).
Utilizing an in-house developed triple-add functional calcium
mobilization assay, we identified multiple modulators of mGlu5,
including—agonists, antagonists, and potentiators.17 This effort re-
sulted in 1400 confirmed PAMs, including 63 with potency below
500 nM.17 Amongst these potent lead structures several, including
VU0092273, were found to contain a biphenyl acetylene moiety
with exceptional ligand efficiency (LE) approaching 0.5 (Fig. 2).17
An optimization campaign around VU0092273 followed, focus-
ing on incorporation of water solubilizing groups, leading to
VU0360172, the first orally active mGlu5 PAM to be efficacious in
an in vivo preclinical antipsychotic model.17 In parallel to these
studies, we investigated structurally constrained analogs of these
phenyl and nicotinyl amides in order to understand their general
activity as PAMs and also as a strategy to mitigate potential
amidase activity that might metabolize amides similar to
VU0092273 and VU0360172.17 In this Letter we describe the syn-
thesis, SAR, and in vivo behavioral profile for three chemically dis-
tinct bicyclic scaffolds.22
We envisioned initially exploring cyclic constraints of the linear
amide scaffolds, VU0092273 and VU0360172, including dihydro-
isoquinolinones (9), dihydronaphthyridinones (10), phthalimides
(11), and isoindolinones (12) (Fig. 2) in conjunction with evaluat-
ing alternate caps (R1) of the lactam NH and aryl moieties (R2). Syn-
thetically all analogs were prepared from the parent bicylic
scaffolds via a Sonagashira coupling reaction using the appropriate
halogen precursors 13 and functionalized phenyl acetylene mono-
mers (Scheme 1). N-Alkyl congeners were subsequently prepared
using standard alkylation conditions as shown.
Initially, we prepared a library of dihydroisoquinolinones (9),
wherein an unsubstituted phenyl moiety was held constant for
R2, and the lactam NH was substituted with various R1 moieties.
This bicyclic constraint proved to be highly beneficial, affording po-
tent and efficacious PAMs and ago-PAMs, defined as PAMs with
⇑
Corresponding author.
E-mail address: shaun.stauffer@vanderbilt.edu (S.R. Stauffer).
0960-894X/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2011.01.044

R. Williams et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1350–1353
1351
Cl
O
H
N
O
N
F
N
F
N
N
HN
OH
N
CN
O
O
1, DFB
2, CPPHA
3, CDDPB
O
N
NHCH3
N
O
NRR'
O
N
F
X
N
N
F
(X = CH or N)
4, ADX47273
5
6
O
F
O
O
CN
N
N
H
N
F
O
7, VU0357121
8, VU0364289
Figure 1. Prototype and recent mGlu5 positive allosteric modulators.
O
O
maximal responses (53–97% of the response elicited by a maximal
concentration of glutamate, herein described as % Glu Max) and
leftward fold-shifts of a full glutamate concentration–response
curve (5.7–11.8Â). Encouraged by the in vitro profile, several dihy-
droisoquinolinones (9) were scaled-up and evaluated in our tier
one, single-point pharmacodynamic assay, amphetamine-induced
hyperlocomotion (AHL), a standard preclinical assay predictive of
antipsychotic acitivity.10,11 Compounds 9a, 9c, and 9f all displayed
significant reversal of amphetamine-induced hyperlocomotion at
30 mg/kg ip, and Figure 3 shows representative data obtained with
9c, the N-propyl derivative.
Based on these promising data, we then evaluated a library of
analogs wherein we held the NH constant on the lactam, as in
9a, and surveyed a diverse group of functionalized aryl moieties
in the R2 position (Table 2). Here, all analogs lose potency relative
to 9a, but still afford potent PAMs and ago-PAMs such as the ortho-
F congener 9m (EC50 = 150 nM, 80% Glu Max) and the meta-CH3
derivative 9k (EC50 = 170 nM, 76% Glu Max). Substituents in the
para-position, such as para-OCH3 (9n) or para-Cl (9r) resulted in
N
N
H
OH
N
F
VU0360172
VU0092273
(HTS hit)
mGlu5 EC50 = 16 nM
(Glu Max = 87%)
LE = 0.48
mGlu5 EC50 = 10 nM
(Glu Max = 72%)
LE = 0.48
O
R1
bicyclic constraints
N
additional water
solubilizing groups
X
R2
O
O
O
R1
N
R1
N
R1
N
X
R2
R2
R2
O
inactive compounds (mGlu5 EC50 >10 lM) whereas the smaller
9, X = CH
10, X = N
11
12
fluorine congener 9l afforded a 260 nM PAM. In our acyclic series,
represented by VU0092273 and VU0360172,17 the meta-F deriva-
tive proved optimal, and thus far, the meta-position appeared the
most amenable to substitution and afforded favorable DMPK
disposition.17
Figure 2. Nicotinyl amide and proposed bicyclic constraints 9–12.
varying degrees of apparent agonist activity (Table 1). The NH con-
gener 9a proved to be the most potent and efficacious
(EC50 = 50 nM, 112% Glu Max, 10.8-fold shift) ago-PAM in this
small library.
Functionalization of the lactam NH afforded a number of potent
PAMs and ago-PAMs with EC50s in the 96–600 nM range with good
While many of these novel PAMs were active in AHL, they re-
quired a DMSO-containing vehicle. Thus, future analogs were de-
signed to incorporate a basic amine to improve physiochemical
properties and enable salt formation to enable non-toxic vehicle
formulations. Therefore, we elected to prepare a small library of
dihydronaphthyridinones (10) wherein R2 was meta-F phenyl and
O
O
Pd[PPh ]4 CuI
O
1)
3
1) NaH, RX
0
H
H
oC to rt, DMF
N
R
N
Phenyl acetyelene
N
Br
X
Br
X
X
2) optional alkylation
NaH, RX
2) Pd[PPh3]4 CuI
aryl acetylene
R'
13
9-12
13
0 oC to rt, DMF
Scheme 1. General routes utilized to prepare 9–12.

1352
R. Williams et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1350–1353
Table 1
Table 2
Structures and activities of bicyclic lactam mGlu5 PAMs 9a–i
Pendant aryl SAR of bicyclic PAMs 9i–t
O
O
R1
N
NH
R2
9
9
a
% Glu Maxb
Category
a
Compd
R1
mGlu5 EC50 (nM)
% Glu Maxb
Category
Compd
R2
mGlu5 EC50 (nM)
9j
o-CH3
m-CH3
p-F
610
170
260
150
>10,000
3400
4900
3700
>10,000
470
53
76
81
80
ND
58
53
50
ND
68
59
PAM
Ago-PAM
PAM
Ago-PAM
ND
PAM
PAM
PAM
ND
PAM
9a
9b
9c
9d
9e
H
50
250
160
96
112
53
97
97
90
Ago-PAM
PAM
Ago-PAM
Ago-PAM
Ago-PAM
9k
91
9m
9n
9o
9p
9q
9r
CH3
n-Pr
n-Bu
Bn
o-F
P-CH3O
m-CH3O
m-CH3, p-F
o-CI
p-CI
m-CI
550
9f
180
270
69
91
77
Ago-PAM
Ago-PAM
PAM
9g
9h
4000
N
N
9s
9t
p-F, o-F
850
PAM
O
9i
3600
84
PAM
a
EC50s are the average of three determinations and are reproducible with a
coefficient of variation of 0.3.
a
EC50s are the average of three determinations and are reproducible with a
coefficient of variation of 0.3.
b
Determined at 30 lM test compound wherein %max vehicle is 10–30%.
b
Determined at 30 lM test compound wherein %max vehicle is 10–30%.
Table 3
Structures and activities of dihydronaphthyridinones 10
O
R1
N
N
F
10
R1
mGlu5 EC50 (nM)/IC50
% Glu Maxb
Category
a
Compd
10a
10b
10c
10d
H
290
170
54
72
34
40
46
PAM
CH3
i-Bu
n-Bu
Partial antag
Weak PAM
Weak PAM
56
10e
10f
660
130
34
53
Partial antag
PAM
a
Figure 3. Reversal of amphetamine-induced hyperlocomotion with bicyclic Glu5
PAMs 9c at a dose of 30 mg/kg ip.
EC50s and IC50s are the average of three determinations and are reproducible
with a coefficient of variation of 0.3.
b
Glu Max is relative to vehicle/EC20 (PAM) or vehicle/EC80 glutamate (antagonist)
window.
R1 was varied (Table 3). Surprisingly, this effort uncovered an
apparent ‘molecular switch.14–16 that modulated the mode of phar-
macology—a first in this class of mGlu5 PAMs.22 Again PAMs, 10a,
10c, 10d, and 10f, all lost potency and significant efficacy relative
to 9a; however, the N-CH3 (10b) and N-cyclopropylmethyl (10e)
congeners proved to be partial antagonists with IC50s of 170 and
660 nM, respectively. Thus, with slight structural changes, a rea-
sonably potent PAM 10a, with a free NH, can be converted into a
partial antagonist (10b) of comparable potency via N-methylation.
These data once again highlight the challenges in developing SAR
for MPEP-site allosteric ligands.
In parallel, we were exploring the impact of constriction of the
six-membered lactam ring to the corresponding five-membered
homologs generating two-dimensional libraries of phthalimides
(11) and isoindolinones (12). The chemistry to access these analogs
was the same as that shown in Scheme 1, and allowed for diversity
at both R1 and R2. As shown in Table 4, the library of phthalimides
11 was highly productive, affording PAMs with EC50s ranging from
congener is comparable in potency (EC50 = 12 nM, 93% Glu Max).
The introduction of a basic amine, as in 11b–11d, was unproduc-
tive, leading to 170- to >1000-fold loss in potency relative to
11a. In addition, the meta-fluorophenyl derivative 11e was again
potent (EC50 = 35 nM, 99% Glu Max), but in this series, 11f and
11g were also reasonable mGlu5 PAMs.
Finally, we deleted one carbonyl of the phthalimide 11 to gen-
erate a small set of isoindolinone analogs 12. This modification also
proved productive, affording mGlu5 PAMs in the 50–350 nM range
(Table 5), but with diminished efficacy relative to phthalimide ana-
logs 11. As anticipated, the unfunctionalized congener 12a
(EC50 = 51 nM, 69% Glu Max) and the meta-fluorophenyl analog
12c (EC50 = 66 nM, 71% Glu Max) proved to be the best in this ser-
ies. However, unlike the six-membered lactam series, both the
ortho- and para-fluorophenyl derivative were reasonable mGlu5
PAMs (EC50s of 200 and 350 nM, respectively).
5.9 to 5.7 lM. Compound 11a, wherein both R1 and R2 are H,
represents the most potent mGlu5 PAM reported to date
(EC50 = 5.9 nM, 104% Glu Max), and 11h, the ortho-fluorophenyl
In summary, we introduced three types of cyclic constraints
into our acyclic amide scaffolds, VU0092273 and VU0360172,

R. Williams et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1350–1353
1353
Table 4
the subject of a comprehensive in vitro molecular pharmacology,
electrophysiology, occupancy, and in vivo pharmacology study that
will be published shortly.
Structures and activities of phthalimides 11
O
References and notes
N
R1
R2
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Jr.; Sur, C.; Kinney, G. G. Curr. Top. Med. Chem. 2006, 8, 771.
O
2. Meltzer, H. Y. Biol. Psychiatry 1999, 46, 1321.
11
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N. L.; Xiang, Z.; Zhang, Y.; Jones, P. J.; Lindsley, C. W.; Olive, M. F.; Conn, P. J.
Neuropsychopharmacol. 2009, 34, 2057.
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W.; Sur, C.; Pettibone, D. J.; Conn, J.; Williams, D. L. Mol. Pharmacol. 2003, 64,
731.
8. O’Brien, J. A.; Lemaire, W.; Wittmann, M.; Jacobson, M. A.; Ha, S. N.; Wisnoski,
D. D.; Lindsley, C. W.; Schaffhauser, H. J.; Rowe, B.; Sur, C.; Duggan, M. E.;
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a
Compd
R1
H
R2
mGluR5 EC50
(nM)
% Glu
Maxb
Category
11a
11b
H
H
5.9
104
Ago-PAM
PAM
870
40
N
N
O
11c
11d
H
H
900
76
44
PAM
PAM
5700
N
11e
11f
H
H
m-F
m-F,
p-F
p-F
o-F
35
170
99
84
Ago-PAM
PAM
11g
11h
H
H
160
12
88
93
PAM
Ago-PAM
a
11. Kinney, G. G.; O’Brien, J. A.; Lemaire, W.; Burno, M.; Bickel, D. J.; Clements, M.
K.; Chen, T. B.; Wisnoski, D. D.; Lindsley, C. W.; Tiller, P. R.; Smith, S.; Jacobson,
M. A.; Sur, C.; Duggan, M. E.; Pettibone, D. J.; Conn, P. J.; Williams, D. L. J.
Pharmacol. Exp. Ther. 2005, 313, 199.
EC50s are the average of three determinations and are reproducible with a
coefficient of variation of 0.3.
b
Determined at 30 lM test compound wherein %max vehicle is 10–30%.
12. Le Poul, E.; Bessis, A. S.; Lutgens, R.; Bonnet, B.; Rocher, J. P.; Epping-Jordan, M.;
Mutel, V. 5th International Metabotropic Glutamate Receptors Meeting, 2005;
Taormina, Italy.
13. Engers, D. W.; Rodriguez, A. L.; Williams, R.; Hammond, A. S.; Venable, D.;
Oluwatola, O.; Sulikowski, G. A.; Conn, P. J.; Lindsley, C. W. Chem. Med. Chem.
2009, 4, 505.
Table 5
Structures and activities of isoindolinones 12
14. Lamb, J. P.; Engers, D. W.; Niswender, C. M.; Rodrigeuz, A. L.; Venable, D. F.;
Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett., available online:
doi:10.1016/j.bmcl.2010.11.119.
O
15. Sharma, S.; Rodriguez, A.; Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett.
2008, 18, 4098.
16. Sharma, S.; Kedrowski, J.; Rood, J. M.; Smith, R. L.; Jones, C. K.; Rodriguez, A. L.;
Conn, P. J.; Lindsley, C. W. J. Med. Chem. 2009, 52, 4103.
N
H
R2
17. Rodriguez, A. L.; Grier, M. D.; Jones, C. K.; Herman, E. J.; Kane, A. S.; Smith, R. L.;
Williams, R.; Zhou, Y.; Marlo, J. E.; Days, E. L.; Blatt, T. N.; Jadhav, S.; Menon, U.;
Vinson, P. N.; Rook, J. M.; Stauffer, S. R.; Niswender, C. M.; Lindsley, C. W.;
Weaver, C. D.; Conn, P. J. Mol. Pharm. 2010, 78, 1105.
12
a
Compd
R2
mGluR5 EC50 (nM)
% Glu Maxb
Category
18. Conn, P. J.; Lindsley, C. W.; Weaver, C. W.; Rodriguez, A. L.; Niswender, C. M.;
Jones, C. K.; Williams, R. Benzamide derivatives as mGluR5 positive allosteric
modulators and their preparation, pharmaceutical compositions and use in the
treatment of diseases. WO 151184, 2008.
12a
12b
12c
12d
H
51
200
66
69
67
71
60
Ago-PAM
PAM
PAM
o-F
m-F
p-F
350
PAM
19. Hammond, A. S.; Rodriguez, A. L.; Townsend, S. D.; Niswender, C. M.; Gregory,
K. J.; Lindsley, C. W.; Conn, P. J. ACS Chem. Neurosci. 2010, 1, 702.
20. Zhou, Y.; Manka, J.; Rodriguez, A. L.; Weaver, C. D.; Jones, C. K.; Conn, P. J.;
Lindsley, C. W.; Stauffer, S. R. ACS Med. Chem. Lett. 2010, 1, 433.
21. Xiong, H.; Brugel, T. A.; Balestra, M.; Brown, D. G.; Brush, K. A.; Hightower, C.;
Hinkley, L.; Hoesch, V.; Kang, J.; Koether, G. M.; McCauley, J. P., Jr.; McLaren, F.
M.; Panko, L. M.; Simpson, T. R.; Smith, R. W.; Woods, J. M.; Brockel, B.;
Chhajlani, V.; Gadient, R. A.; Spear, N.; Sygowski, L. A.; Zhang, M.; Arora, J.;
Breysse, N.; Wilson, J. M.; Isaac, M.; Slassi, A.; King, M. M. Bioorg. Med. Chem.
Lett. 2010, 20, 7381.
22. For studies on a closely related bicyclic ketone series of 7,8-dihydroquinolin-
5(6H)-one mGlu5 modulators see: Vandejevs, M.; Jatzke, C.; Renner, S.; Müller,
S.; Hechenberger, M.; Bauer, T.; Klochkova, A.; Pyatkin, I.; Kazyulkin, D.;
Aksenova, E.; Shulepin, S.; Timonina, O.; Haasis, A.; Gutcaits, A.; Parsons, C. G.;
Kauss, V.; Weil, T. J. Med. Chem. 2008, 51, 634.
a
EC50s are the average of three determinations and are reproducible with a
coefficient of variation of 0.3.
b
Determined at 30 lM test compound wherein %max vehicle is 10–30%.
and developed four series, 9–12, of highly potent and efficacious
(EC50s as low as 5.9 nM, >100% Glu Max) mGlu5 PAMs and ago-
PAMs. Importantly, several novel compounds were centrally active
and displayed significant reversal in an amphetamine-induced
hyperlocomotion assay, a preclinical assay predictive of antipsy-
chotic efficacy. In addition, we identified a subtle ‘molecular
switch’ within scaffold 10 that engendered both PAM and partial
antagonist activities. Key compounds with the 9–12 series are