3102
D. A. Barda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3099–3102
Table 2. EC50 values for mGluR2 potentiation of compounds 18a–t
Annu. Rep. Med. Chem. 1997, 32, 1; (b) Schoepp, D. D.;
Jane, D. E.; Monn, J. A. Neuropharmacology 1999, 38,
1431.
OR1
2. (a) 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; (b) Monn, J. A.; Valli, M. J.; Massey,
S. M.; Hansen, M. M.; Kress, T. K.; Wepsiec, J. P.;
Harkness, A. R.; Grutsch, J. L.; Wright, R. A.; Johnson, B.
G.; Andis, S. L.; Kingston, A. E.; Tomlinson, R.; Lewis, R.;
Griffey, K. R.; Tizzano, J. P.; Schoepp, D. D. J. Med.
Chem. 1999, 42, 1027; (c) Schoepp, D. D.; Wright, R. A.;
Levine, L. R.; Gaydos, B.; Potter, W. Z. Stress 2003, 6, 189.
3. Kingston, A. E.; Ornstein, P. L.; Wright, R. A.; Johnson, B.
G.; Mayne, N. G.; Burnett, J. P.; Belagaje, R.; Wu, S.;
Schoepp, D. D. Neuropharmacology 1998, 37, 1.
4. (a) Knoflach, F.; Mutel, V.; Jolidon, S.; Kew, J. N. C.;
Malherbe, P.; Vieira, E.; Wichmann, J.; Kemp, J. A. Proc.
Natl. Acad. Sci. U.S.A. 2001, 98, 13402; (b) Urwyler, S.;
Mosbacher, M.; Lingenhoel, K.; Heid, J.; Froestl, W.;
Bettler, B.; Kaupmann, K. Mol. Pharm. 2001, 60, 963; (c)
Gasparini, F.; Kuhn, R.; Pin, J.-P. Curr. Opin. Pharmacol.
2002, 2, 43.
5. (a) Johnson, M. P.; Baez, M.; Jagdmann, G. E., Jr.; Britton,
T. C.; Large, T. H.; Callagaro, D. O.; Tizzano, J. P.; Monn,
J. A.; Schoepp, D. D. J. Med. Chem. 2003, 46, 3189; (b)
Britton, T.; Barda, D.; Hornback, W.; Jagdmann, G. E.;
Henry, S.; Fichtner, M.; Wang, Z.-Q.; Coleman, D.;
Chenoweth, D.; Vaught, G.; Fivush, A.; Dressman, B.;
White, R.; Milot, G.; Herr, R. J.; Burry, L.; Johnson, M.
P.; Large, T.; Monn, J.; Schoepp, D. Neuropharmacology
2002, 43, 279.
N
S
O
O
N
R2
Compound
R1
R2
mGluR2
Potentiator
EC50 (nM)
18a
18b
18c
18d
18e
18f
18g
18h
18i
Ph
Bn
CH3
360
620
440
140
1600
2100
100
32
CF3
CH3
CF3
CH3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Bn
CF3
CF3
CH3
CH2CF3
CH(CH3)2
CH2CH(CH3)2
27
18
18j
CH(CH3)CH2CH3
CH(CH3)CH2CH2CH3
CH(CH2CH3)2
18k
18l
14
16
18m
18n
18o
18p
18q
18r
18s
CH2CH(CH3)CH2CH3
CH(CH2)3
CH(CH2)4
17
36
24
29
CH(CH2)5
CH2CO2CH2CH3
CH(CH3)CO2CH2CH3
C(CH3)2CO2CH2CH3
640
230
88
Limited pharmacokinetic data is available on the com-
pounds in these series, although they tended to show
relatively low plasma exposure, after oral dosing. For
example after 14b and 18d were administered at 20 mg/
kg p.o. in rats, only low concentrations of compound
were detected in plasma (Cmax ¼ 61 and 100 ng/mL,
respectively).
6. (a) Johnson, K.; Dieckman, D.; Britton, T.; Johnson, M.;
Jagdmann, E.; Monn, J.; Barda, D.; Henry, S.; Chenoweth,
D.; Coleman, D.; Schoepp, D. Neuropharmacology 2002,
43, 291; (b) Johnson, M.; Baez, M.; Britton, T.; Jagdmann,
G. E., Jr.; Johnson, K.; Johnson, B.; Hornback, W.; Large,
T.; Nisenbaum, E.; Tizzano, J.; Monn, J.; Schoepp, D.
Neuropharmacology 2002, 43, 291; (c) 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, 798; (d) 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.; Pinker-
ton, A. B.; Vernier, J.-M.; Bristow, L. J. Neuropsychophar-
macology 2003, 28, 1622.
7. As an example of the subtype selectivity of these com-
pounds, LY181837 showed no potentiation at the mGlu
subtypes tested: 1, 3, 4, 5, and 8, up to 12.5 lM. mGluR
subtype selectivity was also monitored for representative
compounds from this series. In none of these cases did we
find activity at any of the other mGlu receptor subtypes at
concentrations up to 12.5 lM.
These studies provided us with an understanding of the
structural requirements for mGlu2 activity in this series
and ultimately with highly potent selective mGlu2
potentiators for further in vitro and in vivo studies.
Acknowledgements
We thank Dr. Karl Dahnke and George E. Novak for
their help with the synthesis of intermediates.
References and notes
8. Each final product and synthetic intermediate described
was fully characterized. All spectral data were consistent
with the assigned structures.
1. For recent reviews on the pharmacology of Metabotropic
Glutamate Receptors see: (a) Monn, J. A.; Schoepp, D. D.