Acyl dihydropyrazolo[1,5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators

被引：5

作者：

Malosh, Chrysa ^{[1
,2
,3
,4
]}

Turlington, Mark ^{[1
,2
,3
,4
]}

Bridges, Thomas M. ^{[1
,2
,3
]}

Rook, Jerri M. ^{[1
,2
,3
]}

Noetzel, Meredith J. ^{[1
,2
,3
]}

Vinson, Paige N. ^{[1
,2
,3
]}

Steckler, Thomas ^{[5
]}

Lavreysen, Hilde ^{[5
]}

Mackie, Claire ^{[6
]}

Bartolome-Nebreda, Jose M. ^{[7
]}

Conde-Ceide, Susana ^{[7
]}

Martinez-Viturro, Carlos M. ^{[7
]}

Piedrafita, Maria ^{[7
]}

Sanchez-Casado, M. Rosa ^{[7
]}

Macdonald, Gregor J. ^{[5
]}

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

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

Niswender, Colleen M. ^{[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, Dept Pharmacol, Med Ctr, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Vanderbilt Ctr Neurosci Drug Discovery, Med Ctr, 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] Janssen Res & Dev, Neurosci, B-2340 Beerse, Belgium

[6] Janssen Res & Dev, Discovery Sci ADME Tox, Toledo 45007, Spain

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 22期

关键词：

Metabotropic glutamate receptor 5 (mGlu(5)); Positive allosteric modulator (PAM); NMDA-RECEPTOR; DISCOVERY; SERIES; SAR;

D O I：

10.1016/j.bmcl.2015.10.009

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the optimization of a series of metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) from an acyl dihydropyrazolo[1,5-a]pyrimidinone class. Investigation of exocyclic amide transpositions with this unique 5,6-bicyclic core were conducted in attempt to modulate physicochemical properties and identify a suitable backup candidate with a reduced half-life. A potent and selective PAM, 1-(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl) ethanone (9a, VU0462807), was identified with superior solubility and efficacy in the acute amphetamine-induced hyperlocomotion (AHL) rat model with a minimum effective dose of 3 mg/kg. Attempts to mitigate oxidative metabolism of the western phenoxy of 9a through extensive modification and profiling are described. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：5115 / 5120

页数：6

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