ACS Medicinal Chemistry Letters
Letter
(
14) Hiyoshi, T.; Marumo, T.; Hikichi, H.; Tomishima, Y.; Urabe,
A.; Drinkenburg, W.; Mackie, C.; Trabanco, A. A. Discovery of 1,4-
Disubstituted 3-Cyano-2-pyridones: A New Class of Positive Allosteric
Modulators of the Metabotropic Glutamate 2 Receptor. J. Med. Chem.
2012, 55, 2388−2405.
H.; Tamita, T.; Iida, I.; Yasuhara, A.; Karasawa, J.; Chaki, S.
Neurophysiologic and Antipsychotic Profiles of TASP0433864, a
Novel Positive Allosteric Modulator of Metabotropic Glutamate 2
Receptor. J. Pharmacol. Exp. Ther. 2014, 351, 642−653.
(29) Lavreysen, H.; Langlois, X.; Ahnaou, A.; Drinkenburg, W.; te
Riele, P.; Biesmans, I.; Van der Linden, I.; Peeters, L.; Megens, A.;
Wintmolders, C.; Cid, J. M.; Trabanco, A. A.; Andres, J. I.;
Dautzenberg, F. M.; Lutjens, R.; Macdonald, G.; Atack, J. R.
Pharmacological Characterization of JNJ-40068782, a New Potent,
Selective, and Systemically Active Positive Allosteric Modulator of the
mGlu2 Receptor and its Radioligand [3H]-JNJ-40068782. J.
Pharmacol. Exp. Ther. 2013, 346, 514−527 and references therein..
(30) Dhanya, R.-P.; Sheffler, D. J.; Dahl, R.; Davis, M.; Lee, P. S.;
Yang, L.; Nickols, H. H.; Cho, H. P.; Smith, L. H.; D’Souza, M. S.;
Conn, J. P.; Der-Avakian, A.; Markou, A.; Cosford, N. D. P. Design
and Synthesis of Systemically Active Metabotropic Glutamate Subtype
2- and −3 (mGlu2/3) Receptor Positive Allosteric Modulators
(PAMs): Pharmacological Characterization and Assessment in a Rat
Model of Cocaine Dependence. J. Med. Chem. 2014, 57, 4154−4172
and references therein..
(
15) Woolley, M. L.; Pemberton, D. J.; Bate, S.; Corti, C.; Jones, D.
N. C. The mGlu2 but not the mGluR3 Receptor Mediates the Actions
of the mGluR2/3 Agonist, LY379268, in Mouse Models Predictive of
Antipsychotic Activity. Psychopharmacology 2008, 196, 431−440.
(
16) Fell, M. J.; Svensson, K. A.; Johnson, B. G.; Shoepp, D. D.
Evidence for the Role of mGlu2 not mGlu3 Receptors in the
Preclinical Antipsychotic Pharmacology of the mGlu2/3 Receptor
Agonist LY404039. J. Pharmacol. Exp. Ther. 2008, 326, 209−217.
(
17) Pin, J. P.; Parmentier, M. L.; Prezeau, L. Positive Allosteric
Modulators for γ-Aminobutyric Acid (B) Receptors Open New Routes
for the Development of Drugs Targeting Family 3 G-Protein-Coupled
Receptors. Mol. Pharmacol. 2001, 60, 881−884.
(
18) Arrington, K. L.; Dudkin, V.; Layton, M. E.; Pero, J. E.; Reif, A.
J. Preparation of 5-Substituted 1,3-Dihydro-2H-imidazo[4,5-b]-
pyridine-2-one Derivatives as Positive Allosteric Modulators of
mGluR2 for Therapy. U.S. Patent 0210768, 2013.
(31) Grimm, S. W.; Einolf, H. J.; Hall, S. D.; Ke, K.; Lim, H.-K.; Ling,
K.-H. J.; Lu, C.; Nomeir, A. A.; Seibert, E.; Skordos, K. W.; Tonn, G.
R.; Van Horn, R.; Wang, R. W.; Wong, Y. N.; Yang, T. J.; Obach, R. S.
The Conduct of in Vitro Studies fo Address Time-Dependent
Inhibition of Drug-Metabolizing Enzymes: A Perspective of the
Pharmaceutical Research and Manufacturers of America. Drug Metab.
Dispos. 2009, 37, 1355−1370 and references therein..
(
19) Stauffer, S. R.; Steinbeiser, M. A. Pd-catalyzed Amination in a
Polar Medium: Rate Enhancement, Convenient Product Isolation, and
Tandem Suzuki Cross-Coupling. Tetrahedron Lett. 2005, 46, 2571−
2575 and references therein..
(
20) Sunden, H.; Ibrahem, I.; Eriksson, L.; Cordova, A. Direct
Catalytic Enantioselective Aza-Diels-Alder Reactions. Angew. Chem.
(
32) The reduced analogue of compound 21 was 20-fold less potent
mGluR2 pot. EC50 = 322 nM).
33) For more details, see: Layton, M. E.; Pero, J. E.; Rodzinak, K. J.;
2
(
(
005, 117, 4955−4958.
(
21) Decahydroquinoline 8 is a racemic mixture of cis/trans isomers.
22) LLE is defined as pEC50 − cLogP. For more details, see:
(
Rossi, M. A. Preparation of Imidazopyridin-2-one Derivatives as
Potentiators of Metabotropic Glutamate Receptors. WO 2011034741.
Ryckmans, T.; Edwards, M. P.; Horne, V. A.; Correia, A. M.; Owen, D.
R.; Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Rapid
Assessment of a Novel Series of Selective CB(2) Agonists Using
Parallel Synthesis Protocols: A Lipophilic Efficiency (LipE) Analysis.
Bioorg. Med. Chem. Lett. 2009, 19, 4406−4409.
(34) For more details, see: Fiji, H. D.; Kelly, M. J.; Kern, J. C.;
Layton, M. E.; Pero, J. E.; Reif, A. J.; Rossi, M. A. Preparation of
Imidazopyridin-2-one Derivatives as Potentiators of Metabotropic
Glutamate Receptors. U.S. Patent 0350002, 2014.
(
23) All cLogP values presented in this letter are calculated from
ChemAxon JChem for Excel software package based on the following
method: Viswanadhan, V. D.; Ghose, A. K. K.; Revankar, G. R.;
Robins, R. K. Atomic Physicochemical Parameters for Three
Dimensional Structure Directed Quantitative Structure-Activity
Relationships. J. Chem. Inf. Model. 1989, 29, 163−172.
(
24) Rorick-Kehn, L. M.; Johnson, B. G.; Knitowski, K. M.; Salhoff,
C. R.; Witkin, J. M.; Perry, K. W.; Griffey, K. I.; Tizzano, J. P.; Monn, J.
A.; McKinzie, D. L.; Schoepp, D. D. In Vivo Pharmacological
Characterization of the Structurally Novel, Potent, Selective mGlu2/3
Receptor Agonist LY404039 in Animal Models of Psychiatric
Disorders. Psychopharmacology 2007, 193, 121−136.
(
25) Pinkerton, A. B.; Vernier, J.-M.; Schaffhauser, H.; Rowe, B. A.;
Campbell, U. C.; Rodriguez, D. E.; Lorrain, D. S.; Baccei, C. S.;
Daggett, L. P.; Bristow, L. J. Phenyl-tetrazolyl Acetophenones:
Discovery of Positive Allosteric Potentiators for the Metabotropic
Glutamate 2 Receptor. J. Med. Chem. 2004, 47, 4595−4599.
(
26) Galici, R.; Jones, C. K.; Hemstapat, K.; Nong, Y.; Echemendia,
N. G.; Williams, L. C.; de Paulis, T.; Conn, J. P.; Biphenyl-indanone, A.
a Positive Allosteric Modulator of the Metabotropic Glutamate
Receptor Subtype 2, Has Antipsychotic- and Anxiolytic-Like Effects
in Mice. J. Pharmacol. Exp. Ther. 2006, 318, 173−185 and references
therein..
(
27) Trabanco, A. A.; Tresadern, G.; Macdonald, G. J.; Vega, J. A.; de
Lucas, A. I.; Matesanz, E.; Garcia, A.; Linares, M. L.; Alonso de Diego,
S. A.; Alonso, J. M.; Oehlrich, D.; Ahnaou, A.; Drinkenberg, W.;
Mackie, C.; Andres, J. I.; Lavreysen, H.; Cid, J. M. Imidazo [1,2-
a]pyridines: Orally Active Positive Allosteric Modulators of the
Metabotropic Glutamate 2 Receptor. J. Med. Chem. 2012, 55, 2688−
2701.
(
28) Cid, J. M.; Duvey, G.; Tresadern, G.; Nhem, V.; Furnari, R.;
Cluzeau, P.; Vega, J. A.; de Lucas, A. I.; Matesanz, E.; Alonso, J. M.;
Linares, M. L.; Andres, J. I.; Poli, S. M.; Lutjens, R.; Himogai, H.;
Rocher, J.-P.; MacDonald, G. J.; Oehlrich, D.; Lavreysen, H.; Ahnaou,
F
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