Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM)

Journal of Medicinal Chemistry

Volumn 56, Issue 12, 2013, Pages 5208-5212

  Wenthur, Cody J ^a,b   Morrison, Ryan ^a,b   Felts, Andrew S ^a,b   Smith, Katrina A ^a,b   Engers, Julie L ^a,b   Byers, Frank W ^a,b   Daniels, J Scott ^a,b   Emmitte, Kyle A ^a,b,c   Conn, P Jeffrey ^a,b   Lindsley, Craig W ^a,b,c  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^c VANDERBILT UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(2 FLUORO 4 (( 4 METHOXYPHENYL)ETHYNYL)PHENYL)(3 HYDROXYPIPERIDIN 1 YL)METHANONE; AMIDE; DEUTERIUM; GLUCOSE TRANSPORTER 3; ML 337; MYOTONIC DYSTROPHY PROTEIN KINASE; UNCLASSIFIED DRUG;

ALLOSTERISM; ANIMAL EXPERIMENT; ARTICLE; ATOM; CENTRAL NERVOUS SYSTEM; DRUG POTENCY; DRUG SYNTHESIS; IC 50; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ALLOSTERIC REGULATION; ANIMALS; BRAIN; DRUG DISCOVERY; HUMANS; INHIBITORY CONCENTRATION 50; MICE; PIPERIDINES; RATS; RECEPTORS, METABOTROPIC GLUTAMATE; SUBSTRATE SPECIFICITY;

EID: 84879558600     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm400439t     Document Type: Article

References (18)

1. Conn, P. J.; Pin, J.-P. Pharmacology and functions of metabotropic glutamate receptors Annu. Rev. Pharmacol. Toxicol. 1997, 37, 205-237
2. Melancon, B. J.; Hopkins, C. R.; Wood, M. R.; Emmitte, K. A.; Niswender, C. M.; Christopoulos, A.; Conn, P. J.; Lindsley, C. W. Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery J. Med. Chem. 2012, 55, 1445-1464
3. Conn, P. J.; Christopolous, A.; Lindsley, C. W. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders Nature Rev. Drug Discovery 2009, 8, 41-54
4. Conn, P. J.; Lindsley, C. W.; Jones, C. Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia Trends Pharmacol. Sci. 2009, 30, 25-31
5. Robichaud, A. J.; Engers, D. W.; Lindsley, C. W.; Hopkins, C. R. Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics ACS Chem. Neurosci. 2011, 2, 433-449
6. Sheffler, D. J.; Pinkerton, A. B.; Dahl, R.; Markou, A.; Cosford, N. D. P. Recent Progress in the Synthesis and Characterization of Group II Metabotropic Glutamate Receptor Allosteric Modulators ACS Chem. Neurosci. 2011, 2, 382-393
7. Emmitte, K. A. Recent advances in the design and development of novel negative allosteric modulators of mGlu5 ACS Chem. Neurosci. 2011, 2, 411-432
8. 5) ACS Chem. Neurosci. 2011, 2, 450-470
9. Suzuki, G.; Tsukamoto, N.; Fushiki, H.; Kawagishi, A.; Nakamura, M.; Kurihara, H.; Mitsuya, M.; Ohkubo, M.; Ohta, H. In vitro pharmacological characterization of novel isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists J. Pharmacol. Exp. Ther. 2007, 323, 147-156
10. Harrision, P. J.; Lyon, L.; Sartorius, L. J.; Burnet, P. W. J.; Lane, T. A. The group II metabotropic glutamate receptor 3 (mGlu3, GRM3): expression, function and involvement in schizophrenia J. Psychopharmacol. 2008, 22, 308-322
11. 2/3 negative allosteric modulator in rodent models of depression J. Neurogenet. 2011, 24, 152-166
12. Caraci, F.; Molinaro, G.; Battaglia, G.; Giuffrida, M. L.; Riozzi, B.; Traficante, A.; Bruno, V.; Cannella, M.; Mero, S.; Wang, X.; Heinz, B. A.; Nisenbaum, E. S.; Britton, T. C.; Drago, F.; Sortino, M. A.; Copani, A.; Nicoletti, F. Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer's disease: selective activation of mGlu2 receptors amplifies beta-amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective Mol. Pharmacol. 2011, 79, 618-626
13. Sheffler, D. J.; Wenthur, C. J.; Bruner, J. A.; Carrington, S. J. S.; Blobaum, A. L.; Morrison, R. D.; Daniels, J. S.; Niswender, C. M.; Conn, P. J.; Lindsley, C. W. Development of a novel, CNS penetrant metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM Bioorg. Med. Chem. Lett. 2012, 22, 3921-3925
14. Wood, M. R.; Hopkins, C. R.; Brogan, J. T.; Conn, P. J.; Lindsley, C. W. Molecular switches' on allosteric ligands that modulate modes of pharmacology Biochemistry 2011, 50, 2403-2410
15. Monn, J. A.; Valli, M. J.; Massey, S. M.; Hansen, M. M.; Kress, T. J.; Wepsiec, J. P.; Harkness, A. R.; Grutsch, J. L.; Wright, R. A.; Johnson, B. G.; Andis, S. L.; Kingston, A.; Tomlinson, R.; Lewis, R.; Griffey, K. R.; Tizzano, J. P.; Schoepp, D. D. Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors J. Med. Chem. 1999, 42, 1027-1040
16. For MLPCN, please see: http://mli.nih.gov/mli.
17. For information on Ricerca, see: www.ricerca.com.
18. Nelson, S. D.; Trager, W. F. The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity Drug Metab. Dispos. 2003, 31, 1481-1498