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

被引：114

作者：

Roppe, J ^{[1
]}

Smith, ND ^{[1
]}

Huang, DH ^{[1
]}

Tehrani, L ^{[1
]}

Wang, BW ^{[1
]}

Anderson, J ^{[1
]}

Brodkin, J ^{[1
]}

Chung, J ^{[1
]}

Jiang, XH ^{[1
]}

King, C ^{[1
]}

Munoz, B ^{[1
]}

Varney, MA ^{[1
]}

Prasit, P ^{[1
]}

Cosford, NDP ^{[1
]}

机构：

[1] Merck Res Labs, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 19期

关键词：

D O I：

10.1021/jm049828c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The highly potent, selective, and brain-penetrant metabotropic glutamate subtype 5 (mGlu5) receptor antagonists 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (47) and 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (48) are reported. Compound 47 is active in the rat fear-potentiated startle (FPS) model of anxiety with ED50 = 5.4 mg/kg (po) when dosed acutely. In this model the anxiolytic effects of 47 rapidly tolerate on repeated dosing.

引用

页码：4645 / 4648

页数：4

共 20 条

[1] In vivo receptor occupancy of mGlu5 receptor antagonists using the novel radioligand [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine)
Anderson, JJ
Bradbury, MJ
Giracello, DR
Chapman, DF
Holtz, G
Roppe, J
King, C
Cosford, NDP
Varney, MA
[J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 2003, 473 (01) : 35 - 40
[2] [3H]methoxymethyl-3-[(2-methylyl-1,3-thiazol-4-yl)ethynyl]pyridine binding to metabotropic glutamate receptor subtype 5 in rodent brain:: In vitro and in vivo characterization
Anderson, JJ
Rao, SP
Rowe, B
Giracello, DR
Holtz, G
Chapman, DF
Tehrani, L
Bradbury, MJ
Cosford, NDP
Varney, MA
[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2002, 303 (03) : 1044 - 1051
[3] Anxiolytic-like activity of the mGluR5 antagonist MPEP - A comparison with diazepam and buspirone
Brodkin, J
Busse, C
Sukoff, SJ
Varney, MA
[J]. PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 2002, 73 (02) : 359 - 366
[4] BUSSE CS, IN PRESS NEUROPSYCHO
[5] Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice
Chiamulera, C
Epping-Jordan, MP
Zocchi, A
Marcon, C
Cottiny, C
Tacconi, S
Corsi, M
Orzi, F
Conquet, F
[J]. NATURE NEUROSCIENCE, 2001, 4 (09) : 873 - 874
[6] Pharmacology and functions of metabotropic glutamate receptors
Conn, PJ
Pin, JP
[J]. ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 1997, 37 : 205 - 237
[7] 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: A potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity
Cosford, NDP
Tehrani, L
Roppe, J
Schweiger, E
Smith, ND
Anderson, J
Bristow, L
Brodkin, J
Jiang, XH
McDonald, I
Rao, S
Washburn, M
Varney, MA
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (02) : 204 - 206
[8] [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy:: Potent and selective radioligands for the metabotropic glutamate subtype 5 (mGlu5) receptor
Cosford, NDP
Roppe, J
Tehrani, L
Schweiger, EJ
Seiders, TJ
Chaudary, A
Rao, S
Varney, MA
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (03) : 351 - 354
[9] Inhibition of human hepatic CYP isoforms by mGluR5 antagonists
Green, MD
Jiang, XH
King, CD
[J]. LIFE SCIENCES, 2004, 75 (08) : 947 - 953
[10] Altered synaptic plasticity in a mouse model of fragile X mental retardation
Huber, KM
Gallagher, SM
Warren, ST
Bear, MF
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (11) : 7746 - 7750

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