Rational design of 7-arylquinolines as non-competitive metabotropic glutamate receptor subtype 5 antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.06.030

Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave an orally active compound with high affinity for the MPEP binding site.

Full text of DOI:10.1016/j.bmcl.2007.06.030

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4415–4418
Rational design of 7-arylquinolines as non-competitive
metabotropic glutamate receptor subtype 5 antagonists
*
Jared B. J. Milbank, Christopher S. Knauer, Corinne E. Augelli-Szafran,
Annette T. Sakkab-Tan, Kristin K. Lin, Koji Yamagata, Jennifer K. Hoffman,
Nian Zhuang, John Thomas, Paul Galatsis, John A. Wendt, John W. Mickelson,
Roy D. Schwarz, Jack J. Kinsora, Susan M. Lotarski, Korana Stakich,
Kristen K. Gillespie, Wing W. Lam and Abdul E. Mutlib
Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
Received 15 May 2007; revised 4 June 2007; accepted 5 June 2007
Available online 10 June 2007
Abstract—Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave
an orally active compound with high affinity for the MPEP binding site.
Ó 2007 Elsevier Ltd. All rights reserved.
A recurring structural motif in published reports of
1
In an attempt to remove the acetylene as a potential
metabolic liability, we sought to rationally design ana-
logs without it. One approach to this end, that maintains
an approximate relative geometry of the two aryl rings
present in MPEP and MTEP, was to introduce another
ring from either the pyridine or phenyl of MPEP onto
–6
mGluR5 non-competitive antagonists is the acetylene
linker present in the known MPEP (2-methyl-6-(phenyl-
7
ethynyl)-pyridine, 1) and MTEP (3-[2-(2-methyl-4-
8
thiazolyl)ethynyl]pyridine, 2). A major concern with
acetylenes in potential drugs is the possibility of chemi-
cal or metabolic reactivity. Terminal acetylenes are well
1
8
the acetylene (Scheme 1).
9
,10
known to be mechanism-based CYP-inactivators
there is an increasing body of information that suggests
and
Both alternatives were systematically investigated.
Analog 3, derived by connecting in mode A, could be
accessed by Suzuki coupling of commercially available
1
1–13
internal acetylenes can be activated by CYPs
even undergo uncatalyzed addition of glutathione.
Indeed, we found that incubation of MPEP with tri-
or
1
4,15
7-chloroquinaldine and phenylboronic acid under B u¨ ch-
19,20
1
6
ply-labeled glutathione gave compounds with molecu-
lar weights and fragmentations consistent with both
activated and unactivated addition of GSH to the al-
kyne. These events are potential sources of hepatic
or idiosyncratic toxicity.
wald conditions,
while analog 4, derived by connect-
ing in mode B, was readily accessible by Suzuki coupling
of 2-bromo-6-methylpyridine and naphthalene-2-boro-
nic acid. Conceptual annelation of the alkyne with the
phenyl ring produced 4 that was found to be function-
ally inactive at 10 lM in blocking quisqualate-mediated
1
7
S
Me
Me
N
N
A
N
A
Me
Me
N
3
MPEP (1)
MTEP (2)
Me
N
B
B
N
4
Keywords: mGluR5; Antagonist; MPEP.
*
Corresponding author. Tel.: +1 734 622 2637; e-mail:
Jared.Milbank@Pfizer.com
Scheme 1. Potential removal of the MPEP acetylene by introduction
of a phenyl ring.
0
960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.030

4416
J. B. J. Milbank et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4415–4418
2
1
calcium mobilization using FLIPR, whereas annela-
tion of the pyridine onto the alkyne gave 3, that had
an IC50 of 9.0 lM.
(a)
Me
Me
N
N
Cl
Me
Me
N
N
Ar
(b)
(d)
It is known that the activity of MPEP can be modulated
by substitution on the phenyl ring. In particular, some
meta-substituted aryls have shown improved potency
in the MPEP series. For example, a meta methoxy group
(c)
O
B
B(OH)2
O
2
2
gives M-MPEP, which is 3- to 6-fold more potent than
2
3
Scheme 2. Reagents and conditions: (a) ArB(OH)
o-(dicyclohexylphosphino)biphenyl, PO toluene,
b) Pd(OAc) , KOAc, bis(pinacolato)diboron, bis(diisopropylphenyl)imi-
dazolium chloride, THF, reflux, overnight; (c) THF, NaIO , aq. HCl;
d) ArX (X = Cl, Br, or OTf), and either Pd(OAc)
o-(dicyclohexylphosphino)biphenyl, PO
toluene, 100 °C; or
2
,
Pd(OAc)
2
,
MPEP, and meta-cyano substitution gives a 7-fold
5
more potent compound. Since 7-phenylquinoline 3
K
3
4
,
100 °C;
(
2
had an approximately 1000-fold decrease in potency
over MPEP, we investigated this type of readily accessi-
ble variation by way of substituted phenyl boronic acids.
4
(
2
,
K
3
4
,
2 3
Pd(dppf), aq. K CO , DME, 60 °C.
In the case of 7-aryl quinolines, meta-substitution re-
sulted in modulation in potency in the desired direction
duction of
give compound 6, which exhibited a 20-fold improve-
a
meta-cyanomethyl substituent to
(
Table 1). For example, the compound with a
meta-methoxy group (8) had a 111-fold improvement
in potency. Surprisingly, a meta-cyano substituent gave
greater than 1000-fold improvement to give a 7.7 nM
inhibitor (compound 5). Exploration of substitution at
the ortho- and para-positions showed that the methoxy
and cyano groups did not have the same enhancing
effects in these positions (compounds 19–22).
ment in potency (IC50 = 430 nM), since this bears a
similarity to
a
-(cyanomethyl)phenylbenzoxazoles.
previously reported series of
2
4
4
Mindful of the significant enhancing effect of a meta-
cyano and the mild enhancing effects of some other meta
substitutions, we wondered whether combinations of
substituents would lead to additive effects. Although
the Suzuki reaction noted earlier provided great flexibly,
some of the disubstituted phenylboronic acids required
to examine this SAR were not readily available. In these
cases, the sense of the Suzuki coupling could be reversed
Several other changes gave enhanced activity over the
parent phenyl quinoline 3. For example, 3-aza analog
7
1
5
(a potential isostere of cyanophenylquinoline 5) was
7 times more potent and 3-fluoro analog 9 was
-fold more potent. One interesting change is intro-
(
Scheme 2) by conversion of 7-chloroquinaldine to the
-boronic acid. This was accomplished by treatment
with bis(pinacolato)diboron, palladium acetate and
7
Table 1. FLIPR activity for monosubstituted 7-arylquinolines
2
5
bis(diisopropylphenyl)imidazolium chloride and sub-
R
Me
N
0
0
a
FLIPR IC50 (nM)
b
Table 2. FLIPR activity for 3 -cyano 5 -substituted 7-arylquinolines
Compound
R
SEM
MPEP
—
H
0.2
9000
7.7
CN
3
5
6
7
8
9
1200
5.3
350
Me
N
3-CN
3-CH
3-aza
R
2
CN
430
510
860
400
110
200
400
700
900
2100
500
4000
—
a
FLIPR IC50 (nM)
b
Compound
R
SEM
3-OMe
3-F
1800
3400
4760
5800
8700
14000
19000
IA
6
23
24
25
26
27
28
29
30
31
32
33
34
35
H
5-F
7.7
0.8
5.3
0.1
0.5
0.4
0.3
0.4
0.6
0.2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
3-Me
3-Ac
5-Cl
5-Me
5-CN
5-CH
1.4
1.6
3-CH
3-CH
3-Cl
2
OMe
OH
2.0
2
2
OMe
2.0
3-OH
3-OCF
3-CF
5-OMe
5-Br
2.4
13
3
IA
IA
—
—
5-OEt
5-aza
5-SEt
17
23
3
3-CONH
2-CN
2
6
22
9800
4200
16000
IA
3100
1700
300
—
72
75
2-OMe
4-OMe
4-CN
5-OCF
3
18
38
5-O(CH
i
5-O Pr
2
)
2
OMe
82
310
360
1090
12000
70
70
36
37
38
5-OH
5-SO
a
Compounds were measured for potency to inhibit quisqualate stim-
ulated calcium mobilization using FLIPR. The data shown were
obtained using CHO cells stably expressing rat mGlu5 receptors.
Values are geometric means of two or more experiments (IA, inac-
tive; IC50 > 10 lM).
2
Et
i
5-O Bu
100
6000
a
Values are geometric means of two or more experiments (IA, inactive;
IC50 > 10 lM).
SEM is the standard error of the mean of the measurements.
b
b
SEM is the standard error of the mean of the measurements.

J. B. J. Milbank et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4415–4418
4417
sequent cleavage of the pinacolato boronate with perio-
2
6
date. The 3,5-disubstituted benzonitrile precursors
were typically readily available as chlorides, bromides
or triflates and could be coupled under B u¨ chwald or
conventional Suzuki conditions.
Many of these substitutions gave compounds with en-
hanced potency over parent compound 5 (Table 2). In
general, small lipophilic substituents caused enhance-
ments in potency (e.g., F, Cl, Me, OMe). Larger substit-
uents gave modulated reductions in potency. For
example, a bromo substituent gave a 2-fold reduction,
0
Figure 2. Overlay of 3 -cyano MPEP (magenta) and compound 5
green).
(
i
i
whereas the series –OMe, –OEt, –O Pr, –O Bu gave step-
wise reductions in potency to 12 lM. The small, polar
cyano substituent caused an enhancement in potency,
but phenol, a hydrogen-bond donor, caused a significant
loss.
Table 3. Comparison of functional potency and binding affinity for
select compounds
CN
Me
N
R
Given the high functional potency of some of the com-
pounds, we were interested to see if this would translate
into in vivo efficacy. We tested the most potent com-
a
3
[ H]MPEP
Compound
MPEP
R
FLIPR IC50
nM)
b
(
i
binding K (nM)
2
7,28
0.2
0.8
7.7
5.7
22
pound (23) for anxiolytic activity in the Vogel assay.
2
5
3
5-F
H
Notably, at a dose of 10 mg/kg (po), compound 23
showed a statistically significant reversal of punished
drinking behavior compared to concurrent vehicle treat-
ment (Fig. 1). The magnitude of the response was simi-
lar to that of MPEP at the same dose.
72
a
Values from Tables 1 and 2.
Values are means of two or more experiments.
b
this allows for an almost identical trajectory of the
cyano groups.
One remaining question was whether these 7-aryl quino-
lines, which we envisaged as arising from an isosteric
replacement of a linker in MPEP, were in fact binding
to the same site as MPEP itself. A pharmacophoric
29
In a binding assay with radiolabeled MPEP com-
pounds 5 and 23 completely inhibited the binding of
0
overlay of 3 -cyano MPEP and 7-(3-cyanophenyl)-2-
3
[
H]MPEP to rat brain membrane preparations
Table 3). This confirms that compounds 5 and 23 do
methylquinoline (5) (Fig. 2) strongly suggested they
should, since there is a remarkable overlap between
the MPEP pyridine and phenyl rings and the corre-
sponding rings of the 7-arylquinoline. The overlay addi-
tionally shows that the 7-arylquinoline is able to mimic
torsional changes in the acetylene bond of MPEP, and
(
bind to the same site as MPEP.
Overall, we have shown that the potentially toxicophoric
acetylene of MPEP can be replaced by ring fusion to
give 7-arylquinolines. Additional substitution on the
pendant phenyl is required for high potency. Compound
23 is functionally active, potent, has been shown to bind
to the same site as MPEP, and is active in an in vivo
model of anxiety.
100
*
80
60
40
20
0
*
1
00%
References and notes
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*
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similar strategy resulting in many of the same compounds