Discovery of novel heteroarylazoles that are metabotropic glutamate subtype 5 receptor antagonists with anxiolytic activity

Journal of Medicinal Chemistry

Volumn 47, Issue 19, 2004, Pages 4645-4648

  Roppe, Jeffrey ^a   Smith, Nicholas D ^a   Huang, Dehua ^a   Tehrani, Lida ^a   Wang, Bowei ^a   Anderson, Jeffrey ^a   Brodkin, Jesse ^a   Chung, Janice ^a   Jiang, Xiaohui ^a   King, Christopher ^a   Munoz, Benito ^a   Varney, Mark A ^a   Prasit, Petpiboon ^a   Cosford, Nicholas D P ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [4 (1,3 BENZOXAZOL 2 YL) 2 METHOXYPHENYL]ACETONITRILE; 2 METHYL 6 (PHENYLETHYNYL)PYRIDINE; 3 (5 PYRIDIN 2 YL 2H TETRAZOL 2 YL)BENZONITRILE; 3 [(2 METHYL 4 THIAZOLYL)ETHYNYL]PYRIDINE; 3 FLUORO 5 (5 PYRIDIN 2 YL 2H TETRAZOL 2 YL)BENZONITRILE; 3 METHOXY 5 (PYRIDIN 2 YLETHYNYL)PYRIDINE; [2 METHOXY 4 (4 PYRIDIN 2 YL 1,3 OXAZOL 2 YL)PHENYL]ACETONITRILE; BENZOXAZOLE DERIVATIVE; CALCIUM; FURA 2; G PROTEIN COUPLED RECEPTOR; IMIDAZOLE DERIVATIVE; METABOTROPIC RECEPTOR 5; METABOTROPIC RECEPTOR ANTAGONIST; OXADIAZOLE DERIVATIVE; PYRAZOLE DERIVATIVE; PYRROLE DERIVATIVE; TRIAZOLE DERIVATIVE; TRITIUM; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANXIETY; ARTICLE; CALCIUM TRANSPORT; CONDITIONED REFLEX; CONTROLLED STUDY; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; FLUORESCENCE; GENETIC TRANSFECTION; IC 50; NEUROTRANSMISSION; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; TRANQUILIZING ACTIVITY;

ANIMALS; ANTI-ANXIETY AGENTS; MOLECULAR STRUCTURE; RATS; RECEPTORS, METABOTROPIC GLUTAMATE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 4444283656     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm049828c     Document Type: Article

References (20)

1. Conn, P. J.; Pin, J.-P. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 1997, 37, 205-237.
2. Pin, J.-P.; Acher, F. The metabotropic glutamate receptors: Structure, activation mechanism and pharmacology. Curr. Drug Targets: CNS Neural. Disord. 2002, 1, 297-317.
3. Varney, M. A.; Gereau, R. W. I. Metabotropic glutamate receptor involvement in models of acute and persistent pain: Prospects for the development of novel analgesics. Curr. Drug Targets: CNS Neural. Disord. 2002, 1, 283-296.
4. Brodkin, J.; Busse, C.; Sukoff, S. J.; Varney, M. A. Anxiolytic-like activity of the mGluRS antagonist MPEP. A comparison with diazepam and buspirone. Pharmacol., Biochem. Behav. 2002, 73, 359-366.
5. Spooren, W. P. J. M.; Vassout, A.; Neijt, H. C.; Kuhn, R.; Gasparini, F.; et al. Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethyny)pyridine in rodents. J. Pharmacol. Exp. Ther. 2000, 295, 1267-1275.
6. Pile, A.; Klodzinska, A.; Branski, P.; Nowak, G.; Palucha, A.; et al. Multiple MPEP administrations evoke anxiolytic- and anti-depressant-like effects in rats. Neuropharmacology 2002, 43, 181-187.
7. Chiamulera, C.; Epping-Jordan, M. P.; Zocchi, A.; Marcon, C.; Cottiny, C.; et al. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat. Neurosci. 2001, 4, 873-874.
8. Huber, K. M.; Gallagher, S. M.; Warren, S. T.; Bear, M. F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 7746-7750.
9. Cosford, N. D. P.; Tehrani, L.; Roppe, J.; Schweiger, E. J.; Smith, N. D.; et al. 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]pyridine: A Potent and Highly Selective Metabotropic Glutamate Subtype 5 Receptor Antagonist with Anxiolytic Activity. J. Med. Chem. 2003, 46, 204-206.
10. Wang, B.; Vernier, J.-M.; Rao, S. P.; Chung, J.; Anderson, J.; et al. Discovery of novel modulators of metabotropic glutamate receptor subtype-5. Bioorg. Med. Chem. 2004, 12, 17-21.
11. Slassi, A.; Van Wagenen, B. C.; Stormann, T. M.; Moe, S. T.; Sheehan, S. M.; et al. (NPS Pharmaceuticals, Inc.). Preparation of 3-(2-pyridyl)-5-phenyl substituted 1,2,4-oxadiazoles, 1,2-oxazoles and 1,2,4-triazoles as metabotropic glutamate receptor antagonists. PCT Int. Appl.; WO 2002068417, 2002; p 272.
12. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; et al. New aryl/heteroaryl C-N bond cross-coupling reactions via arylboronic acid/cupric acetate arylation. Tetrahedron Lett. 1998, 39, 2941-2944.
13. Strekowski, L.; Kiselyov, A. S. A Highly Regioselective Reaction of W-Fluoropyridinium Salts with Stabilized Sulfur, Oxygen and Nitrogen Nucleophiles: A Convenient Route to 2-Subtituted Pyridines. J. Heterocycl. Chem. 1993, 30, 1361-1364.
14. Smith, N. D.; Huang, D.; Cosford, N. D. P. One-Step Synthesis of 3-Aryl- and 3,4-Diaryl-(1H)-Pyrroles Using Tosylmethyl Isocyanide (TOSMIC). Org. Lett. 2002, 4, 3537-3539.
15. Varney, M. A.; Cosford, N. D. P.; Jachec, C.; Rao, S. P.; Sacaan, A.; et al. SIB-1757 and SIB-1893: selective, noncompetitive antagonists of metabotropic glutamate receptor type 5. J. Pharmacol. Exp. Ther. 1999, 290, 170-181.
16. 3H]-methoxy-PEPy): Potent and selective radioligands for the metabotropic glutamate subtype 5 (mGlu5) receptor. Bioorg. Med. Chem. Lett. 2003, 13, 351-354.
17. 3H]-Methoxymethyl-MTEP binding to metabotropic glutmate receptor subtype 5 in rat brain: in vitro and in vivo characterization. J. Pharmacol. Exp. Ther. 2002, 303, 1044-1051.
18. 3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine). Eur. J. Pharmacol. 2003, 473, 35-40.
19. Busse, C. S.; Brodkin, J.; Tattersall, D.; Anderson, J.; Warren, N.; et al. The Behavioral Profile of the Potent and Selective mGlu5 Receptor Antagonist 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in Rodent Models of Anxiety. Neuropsychopharmacology, in press.
20. Green, M. D.; Jiang, X.; King, C. D.; Inhibition of human hepatic CYP isoforms by mGluR5 antagonists. Life Sci. 2004, 947-953.