3212
A. L. Rodriguez et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3209–3213
F
F
CF3
N
NH2
NH2
NH2
F
O
O
O
O
O
O
N
N
IC50 = 9.3 µM
% Glu Max = 19.4
IC50 > 10 µM
% Glu Max = 36.0
IC50 = 840 nM
% Glu Max = 1.58
29
27
28
F
F
F
MeO
Cl
NH2
NH2
NH2
Br
O
O
O
O
O
O
HO
N
N
N
EC50 = 7.6 µM
% Glu Max = 73.5
EC50 = 6.1 µM
% Glu Max = 32.9
EC50 = 6.5 µM
% Glu Max = 38.3
32
30
31
Figure 5. mGluR5 non-competitive antagonists 27–29 and mGluR5 PAMs 30–32 identified by optimization of HTS lead 12.
F
S
NH2
N
N
N
N
O
O
N
O
O
12
14i
20c
+
+
+
IC50 = 540 180 nM
Ki = 440+40 nM
IC50 = 150 40 nM
Ki = 410+40 nM
IC50 = 820 100 nM
Ki = 840+110 nM
Figure 6. Novel, non-MPEP mGluR5 non-competitive antagonists 12, 14i and 20c that bind at the MPEP allosteric site, but have little or no structural and topological
similarity to MPEP.
mGluR5 (>30 lM vs mGluRs 1 (Group I), 2,3 (Group II) and 4,7,8
Acknowledgments
(Group III)) and displaced [3H]3-methoxy-5-(2-pyridinylethynyl)
pyridine with a Ki of 410 nM—a value comparable to the IC50
(150 nM). Thus, 12 represents a fundamentally new mGluR5
non-competitive antagonist chemotype that inhibits mGluR5 func-
tion by interaction with the MPEP allosteric binding site. Unlike 10
and 11, SAR for this potent series of mGluR5 non-competitive
antagonists was extremely shallow. Out of 36 analogs, only three
analogs 27–29 possessed inhibitory activity, and three analogs dis-
played weak mGluR5 PAM activity 30–32 (Fig. 5). This was the first
example of this mode of pharmacology switch within a non-MPEP
scaffold, and 30–32 represent another novel mGluR5 PAM scaf-
fold.16–21 Thus, a functional HTS approach, coupled with iterative
parallel synthesis, identified and developed three novel series of
potent and selective mGluR5 non-competitive antagonists repre-
sented by 12, 14i and 20c that bind at the MPEP allosteric site,
but share little or no structural or topological similarities to MPEP
(Fig. 6).
In summary, we have identified three novel, non-MPEP series of
selective non-competitive mGluR5 antagonists with IC50s ranging
from 150 nM to 820 nM for the most potent ligands. These novel
mGluR5 ligands bear little or no structural or topological similarity
to MPEP and represent fundamentally new mGluR5 antagonist
chemotypes. Within series 12, chemical optimization was able to
provide both a potent mGluR5 antagonist 12 (IC50 = 150 nM) and
The authors thank NIDA (DA023947-01) and Seaside Thera-
peutics (VUMC33842) for support of our programs in the devel-
opment of mGluR5 non-competitive antagonists and partial
antagonists.
References and notes
1. (a) Schoepp, D. D.; Jane, D. E.; Monn, J. A. Neuropharmacology 1999, 38, 1431;
(b) Conn, P. J.; Pin, J.-P. Annu. Rev. Pharmacol. Toxicol. 1997, 37, 205.
2. (a) Gasparini, F.; Lingenhohl, K.; Stoehr, N.; Flor, P. J.; Heinrich, M.; Vranesic, I.
Neuropharmacology 1999, 38, 1493; (b) Lea, P. M., IV; Faden, A. I. CNS Drug Rev.
2006, 12, 149.
3. Alagille, D.; Baldwin, R. M.; Roth, B. L.; Wroblewski, J. T.; Grajkowska, E.;
Tamagnan, G. D. Bioorg. Med. Chem. Lett. 2005, 15, 945.
4. Roppe, J. R.; Wang, B.; Huang, D.; Tehrani, L.; Kamenecka, T.; Schweiger, E. J.;
Anderson, J. J.; Brodkin, J.; Jiang, X.; Cramer, M.; Chung, J.; Reyes-Manalo, G.;
Munoz, B.; Cosford, N. D. P. Bioorg. Med. Chem. Lett. 2004, 14, 3993.
5. Newman, A. H.; Kulkarni, S. S. Bioorg. Med. Chem. Lett. 2007, 17, 2987.
6. Galatis, P.; Yamagata, K.; Wendt, J. A.; Connolly, C. J.; Mickelson, J. W.; Milbank,
J. B. J.; Bove, S. E.; Knauer, C. S.; Brooker, R. M.; Augelli-Szafran, C. E.; Schwartz,
R. D.; Kinsora, J. J.; Kilgore, K. S. Bioorg. Med. Chem. Lett. 2007, 17, 6525.
7. Newman, A. H.; Kulkarni, S. S. Bioorg. Med. Chem. Lett. 2007, 17, 2074.
8. Eastman, B.; Chen, C.; Smith, N. D.; Poon, S.; Chung, J.; Reyes-Manalo, G.;
Cosford, N. D. P.; Munoz, B. Bioorg. Med. Chem. Lett. 2004, 14, 5485.
9. Bach, P.; Nilsson, K.; Svensson, T.; Baur, U.; Hammerland, L. G.; Peterson, A.;
Wallberg, A.; Osterland, K.; Karis, D.; Boije, M.; Wensbo, D. Bioorg. Med. Chem.
Lett. 2006, 16, 4788.
10. Micheli, F.; Bertani, B.; Bozzoli, A.; Crippa, L.; Cavanni, P.; Fabio, R. D.; Donati,
D.; Marzorati, P.; Merlo, G.; Paio, A.; Pergunni, L.; Zarantonello, P. Bioorg. Med.
Chem. Lett. 2008, 18, 1804.
11. Hammerland, L. G.; Johansson, M.; Mattson, J. P.; Minidis, A. B. E.; Nilsson, K.;
Peterson, A.; Wensbo, D.; Wallberg, A.; Osterlund, K. Bioorg. Med. Chem. Lett.
2006, 16, 2467.
30–32, weak mGluR5 PAMs (EC50s of 6.1–7.6 lM). This represents
the first example of switching modes of pharmacology in a non-
MPEP series of mGluR5 ligands. Further studies in this arena are
in progress and will be reported in due course.