Synthesis and SAR comparison of regioisomeric aryl naphthyridines as potent mGlu5 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.09.083

We describe three novel regioisomeric series of aryl naphthyridine analogs, which are potent antagonists of the Class III GPCR mGlu5 receptor. The synthesis and in vitro and in vivo pharmacological activities of these analogs are discussed.

Full text of DOI:10.1016/j.bmcl.2007.09.083

Bioorganic & Medicinal Chemistry Letters 17 (2007) 6525–6528
Synthesis and SAR comparison of regioisomeric aryl
naphthyridines as potent mGlu5 receptor antagonists
Paul Galatsis,a Koji Yamagata,a John A. Wendt,a,* Cleo J. Connolly,a
John W. Mickelson,a Jared B. J. Milbank,a Susan E. Bove,b
Christopher S. Knauer,b Rachel M. Brooker,b Corinne E. Augelli-Szafran,a
Roy D. Schwarz,b Jack J. Kinsorab and Kenneth S. Kilgoreb
aDepartment of Medicinal Chemistry, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
bDepartments of CNS Biology and Inflammation, Pfizer Global Research & Development, 2800 Plymouth Road,
Ann Arbor, MI 48105, USA
Received 23 July 2007; revised 24 September 2007; accepted 25 September 2007
Available online 29 September 2007
Abstract—We describe three novel regioisomeric series of aryl naphthyridine analogs, which are potent antagonists of the Class III
GPCR mGlu5 receptor. The synthesis and in vitro and in vivo pharmacological activities of these analogs are discussed.
Ó 2007 Elsevier Ltd. All rights reserved.
Non-competitive metabotropic glutamate receptor 5
N
or
R
R
(mGluR5) antagonists are viewed as having promise
against a number of CNS and peripheral diseases
including the treatment of pain, anxiety, gastro-esopha-
geal reflux disease (GERD), Fragile X syndrome, and
Parkinson’s disease.1 The target has attracted much
attention in the search for small non-competitive antag-
onists which can be useful in the treatment of these dis-
ease states.2–13 We have recently disclosed two novel
classes of potent mGlu5 receptor antagonists (Fig. 1)
which utilize heterocyclic ring cores, namely quinoline
2 and pyrido[2,3-d]pyrimidine 3, identified from a
molecular overlay with MPEP (2-methyl-6-(2-phenyle-
thynyl)pyridine) (1).14,15
Me
N
Me
N
Me
N
N
Quinoline
Pyrido[2,3-d]pyrimidine
MPEP
1
2
3
Figure 1.
N
N
R
R
R
N
N
N
N
1,5-Naphthyridine
1,8-Naphthyridine 1,6-Naphthyridine
4
6
5
In addition to 2 and 3, we now disclose three additional
novel classes of mGlu5 receptor antagonists all contain-
ing regioisomeric 1,8-, 1,6-, and 1,5-naphthyridine cores
(4, 5, and 6, respectively) (Fig. 2).
Figure 2.
ily focused on the pendent aryl moiety of the naphthyri-
dine core. In addition, select SAR investigation of the
2-methyl 1,8- and 1,6-naphthyridine derivatives was
explored in analogy to 1.
It has become obvious, from previous reports, that very
potent inhibitors can be prepared by focusing synthetic
efforts to a particular portion of the molecule. Thus,
our SAR exploration of these new scaffolds was primar-
Assembly of these naphthyridine cores utilized three
separate synthetic routes. The 1,8-naphthydrine core
was constructed utilizing a Friedla¨nder reaction.16,17
The desired products 4 were readily prepared by a sim-
Keywords: mGlu5 receptor; Antagonist; 1,5-Naphthyridine; 1,6-Naph-
thyridine; 1,8-Naphthyridine; Rat; Osteoarthritis; Pain.
*
Corresponding author. E-mail: john.a.wendt@pfizer.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.09.083

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P. Galatsis et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6525–6528
ple one step protocol from commercially available
2-aminonicotinaldehyde (7) and a diverse set of aryl
acetophenones (8) (Scheme 1). Overall, the desired
products were isolated in modest to good yields.
The compounds prepared (13–29) were assessed to
compare the biological activity of all three regioisomeric
naphthyridines to determine mGlu5 receptor antago-
nist functional activity. This data is presented in Table
1. While our SAR studies explored many aryl substitu-
tion patterns, we discovered that similar to the quino-
line14 (2) and the pyrido[2,3-d]pyrimidine15 (3) series,
the 3- and 3,5-aryl substitution pattern was generally
the optimal substitution pattern for imparting antago-
nist activity to these new series. The lone exception
was in the 1,8-naphthyridine series, where compound
17 (3,4-di-Me) was the most potent synthesized
(IC50 = 45 nM).
The 7-aryl 1,6-naphthydrines were constructed utilizing
the procedure of Larock and Roesch.18 Commercially
available 2-bromonicotinaldehyde was converted to its
N-tBu imine (9) which underwent a sequential Sonagas-
hiro coupling with an aryl acetylene derivative19 (10)
(Scheme 2). The resulting crude intermediate was
cyclized upon heating in DMF using CuI (1equiv) to
the desired 7-aryl 1,6-naphthydrine (5). This overall
route, while succinct, revealed variable yields (10–80%)
which appeared to be highly dependent on the substitu-
tion on the aryl ring. For example, a 3-cyano moiety on
the aryl ring afforded the desired 1,6-naphthydrine ring
in only a 26% yield.
In general, comparing the data for these three series (4,
5, and 6), reveals less antagonist potency relative to both
the quinoline and the pyrido[2,3-d]pyrimidine series. In
particular, compound 23 and 29 are 10-fold less potent
than their respective pyrido[2,3-d]pyrimidine analogs.15
The SAR between these regioisomeric naphthyridines
seems to reveal that the 1,8-naphthyridine series (4) con-
tains the most potency, highlighted by simple 3-aryl sub-
stitution (14 and 15) which is 10- to 100-fold more
potent relative to comparable 1,5- and 1,6-analogs (19,
25, and 26).
The 1,5-naphthydrine series was constructed utilizing a
Suzuki cross coupling reaction. The desired products 6
were synthesized from a palladium catalyzed cross cou-
pling of intermediate 1120 and an aryl boronic acid
derivative21 (12) (Scheme 3).
Additionally, 2-methyl-7-phenyl-1,8-naphthyridine ana-
logs were constructed from 2-amino-6-methylnicotinal-
dehyde in a reasonable yield using the route from
Scheme 1. Similarly, the 2-methyl 7-aryl 1,6-naphthyri-
dine compounds were constructed from 2-bromo-6-
methylnicotinaldehyde22 using the Larock synthetic
route from Scheme 2.
Table 2 illustrates selected 2-methyl 1,8- and 1,6-naph-
thyridine derivatives (32–44) that were prepared and
tested for mGlu5 receptor antagonist activity. These
Table 1. Functional (FLIPR) activity for select 1,8-(4), 1,6-(5), and
1,5-(6) naphthyridine analogs
N
N
R
R
O
R
R
N
N
N
CHO
N
a
R
+
N
N
N
NH2
4
5
6
7
8
4
a
FLIPR IC50 (nM) Series
Compound
R
Scheme 1. Reagent: (a) L-proline, EtOH reflux.
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
H
1840
115
4
4
4
4
4
5
5
5
5
5
5
5
6
6
6
6
6
3-CN
3-Me
225
67
3,5-diOMe
3,4-diMe
H
45
N
R
a, b
R
N
>30,000
1270
6570
1590
+
N
3-Me
3-Me-5-F
3-CN-5-F
N
Br
9
10
5
3-CN-5-OCH2OMe 468
Scheme 2. Reagents and conditions: (a) cat. PdCl2(PPh3)2, TEA, cat
CuI, 50 °C; (b) CuI, DMF, 100 °C.
3-CN-5-OMe
3,5-diOMe
3-CN
68
6070
18,600
15,700
12,000
>30,000
55
3-Me
3,4-diMe
3,5-diMe
3-CN-5-OMe
N
R
N
(HO)2B
R
a
+
a Compounds were measured for potency to inhibit quisqualate
stimulated calcium mobilization using FLIPR technology. The
data shown were obtained using CHO cells stably expressing rat
mGlu5 receptors. Values are geometric means of two or more
experiments.
N
N
Br
12
Scheme 3. Reagents: (a) cat. Pd(Ph3)4, NaCO3 (aq), toluene reflux.
11
6

P. Galatsis et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6525–6528
6527
Table 2. Functional (FLIPR) activity for selected 2-methyl 1,8-(30)
and 1,6-(31) naphthyridine analogs
revealed that the 2-methyl substitution appears not to
improve the potency relative to the 2-desmethyl tem-
plate. This is highlighted by the similar potencies be-
tween 16 and 36.
N
R
R
N
N
N
The in vivo activity of compound 36 was evaluated (ip,
10 MPK) in the rat monosodium iodoacetate (MIA)
model of osteoarthritis (OA) pain.23,24 The results are
presented in Figure 3. The time course results of a single
dose intraperitoneal administration of 36 revealed a sig-
nificant inhibition of change in hind paw weight distri-
bution versus vehicle at the 2, 4, and 6 h post dose
time points. This effect, although intraperitoneal, was
quite robust which further supports the evidence of the
mGlu5 receptor antagonists as possible agents to allevi-
ate the signs and symptoms of arthritis.
30
31
a
FLIPR IC50 (nM)
Compound
R
H
Series
32
33
34
35
36
37
38
39
40
41
42
43
44
664
480
30
30
30
30
30
30
30
31
31
31
31
31
31
3-CN
3-Me
277
181
3,5-diF
3,5-diOMe
3-Cl
51.7
177
3-Br
H
3-Me
47.9
>30,000
676
In summary, synthetic routes of three regioisomeric
aryl naphthyridine series possessing potent mGluR5
antagonist activity were developed. The overall SAR
studies for these three series illustrate that the antago-
nist activity resides predominantly in the appropriate
substitution of the C3-and C3,5-disubstituted position
of the aryl ring. In general, the 3 regioisomeric naph-
thydrine series do not appear to be as potent as either
the quinoline or the pyrido[2,3-d]pyrimidine series. The
SAR of the 1,8-naphthyridine series appears to reveal
that this regioisomer is more potent than the other
two naphthyridine regioisomers. Additional 2-methyl
substitution onto the 1,8- and 1,6-naphthyridine series
revealed, unlike the quinoline and pyrido[2,3-d]pyrimi-
dine series, a limited potency benefit. In vivo activity
(ip) of compound 35 revealed a robust effect in the
rat MIA model which validates the 7-aryl 1,8-naph-
thyridine series as another new class of promising
mGlu5 receptor antagonists.
3-OMe
3,5-diOMe
7900
345
3-CN-5-OMe
3-Me-5-F
6.19
2930
a Compounds were measured for potency to inhibit quisqualate stim-
ulated calcium mobilization using FLIPR technology. The data
shown were obtained using CHO cells stably expressing rat mGlu5
receptors. Values are geometric means of two or more experiments.
analogs explore the role the methyl moiety has on
potency for these two series.
From the limited SAR shown, it appears the 2-methyl
moiety is beneficial to optimal potency in the 1,6-naph-
thyridine series with 43 being 10x more potent than 23.
Surprisingly, in the 1,8-naphthyridine series, it was
50
40
30
Vehicle (98% Saline, 2% Cremophor; i.p.)
Compound #36 (10 mg/kg; i.p.)
20
*
*
10
0
*
0
2
4
6
Hours Post Dose
Figure 3. On day 14 post MIA injection, rats were assessed for change in hind paw weight distribution (0 h post dose). Rats were then administered
compound 36 or vehicle (ip) and reassessed 2, 4, and 6 h later. Data are expressed as mean SEM. Statistically significant differences were
determined using a one-way analysis of covariance adjusted for multiplicity of statistical testing by Hochberg’s Procedure (*P < 0.05 vs vehicle at
same time point). N = l8 rats per group.

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P. Galatsis et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6525–6528
Schwarz, R.; Kinsora, J.; Lotarski, S.; Stakich, K.;
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