Pyrimidine methyl anilines: Selective potentiators for the metabotropic glutamate 2 receptor

Article abstract of DOI:10.1016/j.bmcl.2004.07.079

Pyrimidine methyl anilines as potent and selective mGlu2 potentiators are described. Findings from the structure-activity-relationship investigations are discussed.

Full text of DOI:10.1016/j.bmcl.2004.07.079

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5071–5074
Pyrimidine methyl anilines: selective potentiators for the
metabotropic glutamate 2 receptor
Essa Hu,a,* Peter C. Chua,a Lida Tehrani,a Johnny Y. Nagasawa,a Anthony B. Pinkerton,a
Blake A. Rowe,b Jean-Michel Vernier,a John H. Hutchinsona and Nicholas D. P. Cosforda
aDepartment of Medicinal Chemistry, Merck Research Laboratories, San Diego, CA 92121, USA
bDepartment of Molecular Profiling, Merck Research Laboratories, San Diego, CA 92121, USA
Received 23 June 2004; revised 29 July 2004; accepted 29 July 2004
Available online 24 August 2004
Abstract—Pyrimidine methyl anilines as potent and selective mGlu2 potentiators are described. Findings from the structure–activ-
ity-relationship investigations are discussed.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
pound 1: LY487379) as potentiators (or positive allos-
teric modulators), which bind to the transmembrane
region instead of the agonist binding pocket in the extra-
cellular domain.5,6 Comparative pharmacological analy-
ses further revealed that selectivity was attributed to
distinct differences in the amino acid sequences of the
mGlu2 and mGlu3 transmembrane regions.7 These re-
ports prompted the current disclosure of the discovery
of novel pyrimidine methyl anilines as selective positive
modulators of mGlu2 receptor.
Abnormally high levels of glutamate, a major excitatory
neurotransmitter in the central nervous system, have
been linked to several neurological diseases, such as Par-
kinsonÕs disease, schizophrenia, HuntingtonÕs chorea,
and AlzheimerÕs disease.1,2 There are two types of gluta-
mate receptors in the CNS: the ionotropic glutamate
(iGlu) receptors and the metabotropic glutamate (mGlu)
receptors. The iGlu receptors are glutamate-gated ion
channels, which mediate fast synaptic transmission.
The mGlu receptors modulate glutamate transmission
by second messenger activation. Excessive accumulation
of glutamate in the perisynaptic extracellular region trig-
gers both group II (mGlu2 and 3) and group III (mGlu4,
6, 7, and 8) receptors to inhibit further release of gluta-
mate.2,3 Thus, stimulation of these presynaptic receptors
could be a therapeutic means to reduce excess glutamate
in the CNS.
OMe
O
N
O
S
O
N
1: LY487379
CF3
2. Structure–activity relationships
Several small molecule agonists that simultaneously
activate both mGlu2 and mGlu3 receptors have been re-
ported.4 A selective mGlu2 receptor agonist, however,
has not yet been identified, presumably due to signifi-
cant homology between the two receptor binding sites.
Recently, selective activation of mGlu2 was reported
using pyridine sulfonamide derivatives (such as com-
In order to gain insight into the binding region of
mGlu2 receptor potentiators, our investigation began
with structure–activity-relationship (SAR) studies of
the pyridyl region of the pyridine sulfonamides, which
was not presented in detail in the recent reports.5
Replacement of the 3-pyridyl moiety on compound 1
with other aromatic rings such as 3-fluorobenzene,
3-thiophene, 3-furan, 2-benzimidazole, 3-nitrobenzene,
3-aminobenze, or 4-imidazole all resulted in complete
loss of potency. Nevertheless, quinoline and pyrimidine
Keywords: Metabotropic glutamate receptor; mGlu2; Potentiator.
*
Corresponding author. Tel.: +1 8582025584; fax: +1 8582025752;
e-mail: essa_hu@merck.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.07.079

5072
E. Huet al. / Bioorg. Med. Chem. Lett. 14 (2004) 5071–5074
Table 1. Quinoline and pyrimidine anilines
Other alkoxy phenyl amine analogs of pyrimidine 6 were
inactive.
Compd
Structure
mGlu2 EC50 lMa
[% potentiation]b
These observations prompted a systematic investigation
of the more potent pyrimidine methyl aniline series,
beginning with the phenyl aryl ether right hand piece
on compound 1 (LY4873739). Gratifyingly, pyrimidine
phenyl ether 9 exhibited better potency than the pyridyl
analog (1) (Table 2). Moving the phenyloxy substituent
to the 3 position (10) enhanced the level of potentiation
with only slight loss of potency. This was in contrast to
the pyridine sulfonamide series, which was reported be
three- to fourfold more potent with the 3-phenyloxy
group than the 4-phenyloxy group.5c Furthermore,
while additional substituents ortho to the phenoxy ring
increased the activity of the pyridine sulfonamides,5c
similar substitutions on the pyrimidine sulfonamide with
bromine (11) or fluorine (12), or methoxy (13) groups
slightly reduced the potency in this series instead. Only
the methyl analog 14 retained the potency and level of
potentiation of 10. Thus, the SAR of the pyrimidine
OMe
O
1
1.70 [52%]
N
S
O
O
N
LY487379
CF3
2
3
4
N
H
O
O
4.30 [41%]
5.20 [40%]
1.00 [18%]
N
CF3
N
H
N
N
N
H
CF3
5
6
7
8
9.60 [68%]
0.19 [26%]
0.71 [31%]
0.54 [43%]
N
N
N
H
N
CF3
N
H
O
N
N
N
N
H
Table 2. Aryloxy substituents and linker modifications
N
N
N
S
R =
N
S
O
O
N
O
O
N
CF3
CF3
a Concentration of compound required to activate 50% of [35S]GTPcS
in the presence of 10lM glutamate as agonist.
b 100% potentiation is defined as [35S]GTPcS activation with 1mM
glutamate alone.
Compd
Structure
mGlu2 EC50 lM
[% potentiation]a
O
9
0.56 [37%]
0.66 [52%]
R
10
R
R
O
substitutions retained some activity (Table 1). Assess-
ment of the efficacy of these compounds was based on
two criteria: the potency (EC50) and the level of potenti-
ation (%) in the GTPcS binding assay (see footnotes
of Table 1). As a point of reference, compound 1
(LY4873739) in our assay gave an EC50 value of
1700nM with 52% potentiation,7a compared with a re-
ported EC50 of 270nM.5b
11
12
13
14
1.10 [40%]
0.86 [46%]
0.76 [62%]
0.63 [53%]
O
Br
R
R
O
O
F
O
Using select right hand pieces described by Barda and
co-workers,5a,c the quinoline and pyrimidine analogs
exhibited some surprising structure–activity trends
(Table 1). Unlike the pyridine sulfonamide series where
the sulfonamide functionality was essential for poten-
cy,5c both quinoline and pyrimidine derivatives in
Table 1 were active as secondary amines. Quinolines 2
and 3 were weakly potent; however, quinoline 4 had a
modest potency of 1.0lM but a low level of potentia-
tion. Pyrimidine methyl aniline 5 had a good level of
potentiation despite its low potency. Both pyrimidines
6 and 7 had submicromolar activity, with compound 6
showing an impressive EC50 of 0.19lM. Interestingly,
the sulfonamide analogs (structures not shown) of active
secondary amines 2–6 were inactive up to 10lM. The
exception was sulfonamide 8, which retained the activity
and level of potentiation of its amine precursor (7).
It should also be noted that the trifluoromethoxy moiety
appeared to be critical for the activity of pyrimidine (6).
R
R
R
O
15
16
0.97 [73%]
1.20 [51%]
CF3
O
O
17
0.81 [39%]
R
O
18
19
20
0.66 [48%]
0.84 [60%]
0.35 [31%]
O
Si
R
R
R
O
O
a See footnotes a and bin Table 1.

E. Huet al. / Bioorg. Med. Chem. Lett. 14 (2004) 5071–5074
5073
O
R
R
b
N
N
S
a
N
N
H
N
H
+
H2N
R
O
O
N
N
N
CF3
21
O
Ph
OTBS
N
N
S
c, d
N
N
S
O
O
O
O
O
N
N
18
17
CF3
CF3
Scheme 1. Reagents and conditions: (a) MeOH, reflux; NaBH4; or NaBH(OAc)3, AcOH, dichloroethane; (b) 2,2,2-trifluoroethanesulfonyl chloride,
pyridine, dichloroethane; (c) TBAF, AcOH; (d) benzoyl chloride.
series exhibited distinct differences from the SAR of the
pyridine series.
4. Conclusion
In conclusion, we have identified pyrimidine methyl ani-
lines as novel mGlu2 potentiators. The most potent
compound in this study (20) was also determined to be
inactive against the mGlu3 receptor up to 10lM
(mGlu3 receptor binding potency and level of potentia-
tion were determined using the same protocol as the
mGlu2 receptor binding assay described in the footnotes
of Table 1). Comparative analyses of the analogs have
revealed these pyrimidines as a distinct series with struc-
ture–activity relationships unlike those previously
reported for the pyridine sulfonamides. In addition,
quinolines (2, 3, 4) and pyrimidines (5, 6, 7) were found
to be active as just secondary amines. The pyrimidine
methyl anilines are useful probes to elucidate the nature
of the mGlu2 transmembrane binding site.
The divergence of SAR between the two series was also
observed with benzyl pyrimidines. ortho Trifluoro-
methylbenzyl and phenyloxymethyl were two right hand
pieces reported to be more potent in the pyridine series
than the phenyl ether right hand piece on compound
9.5c However, when applied to the pyrimidine methyl
aniline series, these moieties reduced the potency of their
pyrimidine sulfonamide analogs (15, 16) even though
their levels of potentiation improved. Interestingly, the
activity was restored by replacing the phenyloxy substit-
uent with a benzoyl group (17) or bulky trialkysi-
lyl group (18), suggesting the presence of a lipophilic
pocket. Indeed, bulky substituents such as cyclopentyl-
oxy (19) and 2-pentyloxy (20) groups produced potent
compounds while their methoxy, and ethoxy analogs
(structures not shown) were inactive. In fact, pyrimidine
20 was the most potent compound (0.35lM) in the
pyrimidine sulfonamide series in this investigation,
even though its level of potentiation was moderate
(sulfonamide 15 had the highest level of potentiation
with 73%).
Acknowledgements
The authors would also like to thank Grace Reyes-
Manalo and Purabi Datta for running the binding
assays and Lorrie Daggett for her input on this paper.
The nature of the right binding region was further eluci-
dated by changing the position of the 2-pentyloxy group
meta to the aniline ring on compound 20. Both para and
ortho substituted 2-pentyloxy pyrimidine sulfonamides
(structures not shown) were inactive. In contrast, para
phenyloxy sulfonamides (9) exhibited potency compara-
ble to its meta phenyloxy analog (10). Therefore, the
binding region para to the aniline phenyl group
appeared to be less tolerant of bulky groups than the
binding region meta to the phenyl group.
References and notes
1. (a) Pin, J.-P.; Acher, F. Curr. Drug Targets––CNS Neurol.
Disorders 2002, 1, 297–317; (b) Choi, D. W. Neuron 1998, 1,
623–634; (c) Olney, J. W. In Glutamate, Cell Death and
Memory; Ascher, P., Choi, D. W., Christen, Y., Eds.;
Springer: New York, 1991; pp 77–101.
2. Bockaert, J.; Fagni, L.; Pin, J.-P. In Glutamate and GABA
Receptors and Transporters; Egebjerg, J., Schousboe, A.,
Krogsgaard-Larsen, P., Eds.; Taylor & Francis: London,
2002; pp 121–150.
3. Scanziani, M.; Salin, P. A.; Vogt, K. E.; Malenka, R. C.;
Nicoll, R. A. Nature 1997, 385, 630–634.
3. Chemistry
4. (a) Levine, L.; Gaydos, B.; Sheehan, D.; Goddarg, A. W.;
Feighner, J.; Potter, W. Z.; Schoepp, D. D. Neuropharma-
cology 2002, 43, 294; (b) Brauner-Osborne, H.; Egebjerg, J.;
Nielsen, E. O.; Madsen, U.; Krogsgaard-Larsen, P. J. Med.
Chem. 2000, 43, 2609–2645; (c) Nakazato, A.; Kumagai, T.;
Sakagami, K.; Yoshikawa, R.; Suzuki, Y.; Chaki, S.; Ito,
H.; Taguchi, T.; Nakanishi, S.; Okuyama, S. J. Med. Chem.
2000, 43, 4893–4909; (d) Monn, J. A.; Valli, M. J.; Massey,
S. M.; Hansen, M. M.; Kress, T. J.; Wepsiec, J. P.;
Harkness, A. R.; Grutsch, J. L., Jr.; Wright, R. A.;
Johnson, B. G.; Andis, S. L.; Kingston, A.; Tomlinson,
The synthesis of these compounds was relatively facile.
In most cases, the fully elaborated aniline was alkylated
by reductive amination with pyrimidine-5-carboxalde-
hyde (21) using either sodium borohydride or sodium
triacetoxyborohydride.8 The sulfonamides were pre-
pared by addition of 2,2,2-trifluoroethanesulfonyl chlo-
ride and an amine base.5 Compound 17 was prepared
by TBAF deprotection of sulfonamide 18 followed by
acylation with benzoyl chloride (Scheme 1).

5074
E. Huet al. / Bioorg. Med. Chem. Lett. 14 (2004) 5071–5074
R.; Lewis, R.; Griffey, K. R.; Tizzano, J. P.; Schoepp, D. D.
Tizzano, D. D.; Monn, J.; Schoepp, D. D. Neuropharma-
cology 2002, 43, 279; (e) Coleman, D. S.; Jagdmann, G. E.,
Jr.; Johnson, E. W.; Johnson, M. P.; Large, T. H.; Monn, J.
A.; Schoepp, D. D.; Tizzano, J. P.; Barda, D. A.; Britton,
T. C.; Dressman, B. A.; Fichtner, M. W.; Henry, S. S.;
Hornback, W. J. International Patent Application WO
2001056990 A2, 2001; Chem. Abstr. 2001, 135, 152723.
6. (a) Lorrain, D. S.; Schaffhauser, H.; Campbell, U. C.;
Baccei, C. S.; Correa, L. D.; Rowe, B.; Rodriguez, D. E.;
Anderson, J. J.; Varney, M. A.; Pinkerton, A. B.; Vernier,
J.-M.; Bristow, L. J. Neuropsychopharmacology 2003, 28,
1622–1632; (b) Johnson, K.; Dieckman, D.; Britton, T.;
Johnson, M.; Jagdmann, E.; Monn, J.; Barda, D.; Henry,
S.; Chenoweth, D.; Coleman, D.; Schoepp, D. Neurophar-
macology 2002, 43, 291; (c) Johnson, M.; Baez, M.; Britton
T.; Jagdman, G. E., Jr.; Johnson, K.; Johnson, B.;
Hornback, W.; Large, T.; Nisenbaum, E.; Tizzano, J.;
Monn, J.; Schoepp, D. Neuropharmacology 2002, 43, 291.
7. (a) Schaffhauser, H.; Rowe, B. A.; Morales, S.; Chavez-
Noriega, L. E.; Yin, R.; Jachec, C.; Rao, S.; Bain, G.;
Pinkerton, A. B.; Vernier, J.-M.; Bristow, L. J.; Varney, M.
A.; Daggett, L. P. Mol. Pharmacol. 2003, 64, 798–810; (b)
Schaffhauser, H.; Rowe, B. A.; Morales, S.; Chavez-
Noriega, L. E.; Yin, R.; Jachec, C.; Rao, S. P.; Bain, G.;
Pinkerton, A. B.; Vernier, J.-M.; Bristow, L. J.; Varney, M.
A.; Daggett, L. P. Mol. Pharmacol. 2003, 64, 1–13.
J. Med. Chem. 1999, 42, 1027–1040; (e) Kozikowski, A. P.;
Araldi, G. L.; Tuckmantel, W.; Pshenichkin, S.; Surina, E.;
Wroblewski, J. T. Bioorg. Med. Chem. Lett. 1999, 9, 1721–
1726; (f) Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright,
R. A.; Salhoff, C. R.; Johnson, B. G.; Howe, T.; Alt, C. A.;
Rhodes, G. A.; Robey, R. L.; Griffey, K. R.; Tizzano, J. P.;
Kallman, M. J.; Helton, D. R.; Schoepp, D. D. J. Med.
Chem. 1997, 40, 528–537; (g) Schoepp, D. D.; Salhoff, C.
R.; Wright, R. A.; Johnson, B. G.; Burnett, J. P.; Mayne,
N. G.; Belagaje, R.; Wu, S.; Monn, J. A. Neuropharmacol-
ogy 1996, 35, 1661–1672.
5. (a) Barda, D. A.; Wang, Z.-Q.; Britton, T. C.; Henry, S. S.;
Jagdmann, G. E.; Coleman, D. S.; Johnson, M. P.; Andis,
S. L.; Schoepp, D. D. Bioorg. Med. Chem. Lett. 2004, 14,
3099–3102; (b) Johnson, M. P.; Baez, M.; Jagdmann, G. E.;
Britton, T. C.; Large, T. H.; Callagaro, D. O.; Tizzano, J.
P.; Monn, J. A.; Schoepp, D. D. J. Med. Chem. 2003, 46,
3189–3192; (c) Barda, D. A.; Britton, T. C.; Hornback, W.
J.; Jagdmann, G. E.; Henry, S. S.; Fichtner, M. W.; Wang,
Z.-Q.; Colemna, D. S.; Chenoweth, D. M.; Vaught, G. M.;
Fivush, A. M.; Herr, R. J.; Burry, L. C.; Johnson, M. P.;
Large, T. H.; Baez, M.; Monn, J. A.; Schoepp, D. D.;
Johnwon, K. W.; Shannon, H. E.; Tizzano, J. P. Poster
Abstracts, Keystone Symposia, Park City, Utah, January
7–12, 2003; ICOS Corporation; (d) Johnson, M. P.; Baez,
M.; Britton, T. C.; Jagdman, G. E., Jr.; Johnson, K. W.;
Johnson, B.; Hornback, W. J.; Large, T.; Nisenbaum, E.;
8. Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G.
Tetrahedron Lett. 1990, 31, 5595–5598.