Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu5)

被引：14

作者：

Turlington, Mark ^{[1
,2
,3
]}

Malosh, Chrysa ^{[1
,2
,3
]}

Jacobs, Jon ^{[1
,2
,3
]}

Manka, Jason T. ^{[1
,2
,3
]}

Noetzel, Meredith J. ^{[1
,2
]}

Vinson, Paige N. ^{[1
,2
]}

Jadhav, Satyawan ^{[1
,2
]}

Herman, Elizabeth J. ^{[1
,2
]}

Lavreysen, Hilde ^{[6
]}

Mackie, Claire ^{[7
]}

Bartolome-Nebreda, Jose M. ^{[8
]}

Conde-Ceide, Susana ^{[8
]}

Luz Martin-Martin, M. ^{[8
]}

Min Tong, Han ^{[8
]}

Lopez, Silvia ^{[8
]}

MacDonald, Gregor J. ^{[6
]}

Steckler, Thomas ^{[6
]}

Daniels, J. Scott ^{[1
,2
,3
]}

Weaver, C. David ^{[1
,5
]}

Niswender, Colleen M. ^{[1
,2
,3
]}

Jones, Carrie K. ^{[1
,2
,3
]}

Conn, P. Jeffrey ^{[1
,2
,3
]}

Lindsley, Craig W. ^{[1
,2
,3
,4
]}

Stauffer, Shaun R. ^{[1
,2
,3
,4
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[3] Vanderbilt Specialized Chem Ctr Probe Dev MLPCN, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Vanderbilt Inst Chem Biol, Nashville, TN 37232 USA

[6] Janssen Res & Dev, Neurosci, B-2340 Beerse, Belgium

[7] Janssen Res & Dev, Discovery Sci ADME Tox, B-2340 Beerse, Belgium

[8] Janssen Res & Dev, Neurosci Med Chem, Toledo 45007, Spain

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 13期

关键词：

IN-VIVO ACTIVITY; RAT BEHAVIORAL-MODELS; ANTIPSYCHOTIC-DRUGS; LEAD DISCOVERY; SCHIZOPHRENIA; MGLUR5; SERIES; SITE; PHARMACOLOGY; SUBTYPE-5;

D O I：

10.1021/jm500259z

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu(5)) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu(5) PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu(5) as well as antagonist activity at mGlu(3). Structure-activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu(5) PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.

引用

页码：5620 / 5637

页数：18

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