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

共 50 条

[1] Cyclopropyl-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5
Lakkaraju, Sirish K.
Mbatia, Hannah
Hanscom, Marie
Zhao, Zaorui
Wu, Junfang
Stoica, Bogdan
MacKerell, Alexander D., Jr.
Faden, Alan I.
Xue, Fengtian
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (11) : 2275 - 2279
[2] Dihydrothiazolopyridone Derivatives as a Novel Family of Positive Allosteric Modulators of the Metabotropic Glutamate 5 (mGlwu5) Receptor
Manuel Bartolome-Nebreda, Jose
Conde-Ceide, Susana
Delgado, Francisca
Iturrino, Laura
Pastor, Joaquin
Angel Pena, Miguel
Trabanco, Andres A.
Tresadern, Gary
Wassvik, Carola M.
Stauffer, Shaun R.
Jadhav, Satyawan
Gogi, Kiran
Vinson, Paige N.
Noetzel, Meredith J.
Days, Emily
Weaver, C. David
Lindsley, Craig W.
Niswender, Colleen M.
Jones, Carrie K.
Conn, P. Jeffrey
Rombouts, Frederik
Lavreysen, Hilde
Macdonald, Gregor J.
Mackie, Claire
Steckler, Thomas
JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (18) : 7243 - 7259
[3] Progress in the Developement of Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2
Trabanco, A. A.
Cid, J. M.
Lavreysen, H.
Macdonald, G. J.
Tresadern, G.
CURRENT MEDICINAL CHEMISTRY, 2011, 18 (01) : 47 - 68
[4] Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)
Stauffer, Shaun R.
ACS CHEMICAL NEUROSCIENCE, 2011, 2 (08): : 450 - 470
[5] Article Photoswitchable positive allosteric modulators of metabotropic glutamate receptor 4 to improve selectivity
Panarello, Silvia
Gonzalez-Diez, Aleix
Berizzi, Alice E.
Malhaire, Fanny
Borras-Tuduri, Roser
Rovira, Xavier
Serra, Carme
Prezeau, Laurent
Pin, Jean-Philippe
Goudet, Cyril
Llebaria, Amadeu
Gomez, Xavier
ISCIENCE, 2024, 27 (06)
[6] Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu5)
Turlington, Mark
Malosh, Chrysa
Jacobs, Jon
Manka, Jason T.
Noetzel, Meredith J.
Vinson, Paige N.
Jadhav, Satyawan
Herman, Elizabeth J.
Lavreysen, Hilde
Mackie, Claire
Bartolome-Nebreda, Jose M.
Conde-Ceide, Susana
Luz Martin-Martin, M.
Min Tong, Han
Lopez, Silvia
MacDonald, Gregor J.
Steckler, Thomas
Daniels, J. Scott
Weaver, C. David
Niswender, Colleen M.
Jones, Carrie K.
Conn, P. Jeffrey
Lindsley, Craig W.
Stauffer, Shaun R.
JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (13) : 5620 - 5637
[7] Tricyclic Thiazolopyrazole Derivatives as Metabotropic Glutamate Receptor 4 Positive Allosteric Modulators
Hong, Sang-Phyo
Liu, Kevin G.
Ma, Gil
Sabio, Michael
Uberti, Michelle A.
Bacolod, Maria D.
Peterson, John
Zou, Zack Z.
Robichaud, Albert J.
Doller, Dario
JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (14) : 5070 - 5081
[8] Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators as Novel Tools for in Vivo Investigation
Keck, Thomas M.
Zou, Mu-Fa
Zhang, Peng
Rutledge, Rebecca P.
Newman, Amy Hauck
ACS MEDICINAL CHEMISTRY LETTERS, 2012, 3 (07): : 544 - 549
[9] Positive Allosteric Modulators (PAMs) of Metabotropic Glutamate Receptor 5 (mGluR5) Attenuate Microglial Activation
Xue, Fengtian
Stoica, Bogdan A.
Hanscom, Marie
Kabadi, Shruti V.
Faden, Alan I.
CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS, 2014, 13 (04) : 558 - 566
[10] Chemical Switch of a Metabotropic Glutamate Receptor 2 Silent Allosteric Modulator into Dual Metabotropic Glutamate Receptor 2/3 Negative/Positive Allosteric Modulators
Schann, Stephan
Mayer, Stanislas
Franchet, Christel
Frauli, Melanie
Steinberg, Edith
Thomas, Mireille
Baron, Luc
Neuville, Pascal
JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (24) : 8775 - 8779

← 1 2 3 4 5 →