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

[21] Fragment-Based Approaches for Allosteric Metabotropic Glutamate Receptor (mGluR) Modulators
Orgovan, Zoltan
Ferenczy, Gyorgy G.
Keseru, Gyorgy M.
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2019, 19 (19) : 1768 - 1781
[22] SAR Studies on mGlu5 Receptor Positive Allosteric Modulators (2003-2013)
Hao, Junliang
Xiong, Hui
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2014, 14 (15) : 1789 - 1841
[23] Identification and optimisation of a series of tetrahydrobenzotriazoles as metabotropic glutamate receptor 5-selective positive allosteric modulators that improve performance in a preclinical model of cognition
Ellard, John M.
Madin, Andrew
Philps, Oliver
Hopkin, Mark
Henderson, Scott
Birch, Louise
O'Connor, Desmond
Arai, Tohru
Takase, Kazuma
Morgan, Louise
Reynolds, David
Talma, Sonia
Howley, Eimear
Powney, Ben
Payne, Andrew H.
Hall, Adrian
Gartlon, Jane E.
Dawson, Lee A.
Castro, Luis
Atkinson, Peter J.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (24) : 5792 - 5796
[24] Combining bioactivity and affinity to design of positive allosteric modulators of the metabotropic glutamate receptor using 3D-QSAR
Hao, Chun-Zhi
Yu, Liang-Min
Xia, Shu-Wei
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2020, 38 (06): : 1880 - 1885
[25] Metabotropic glutamate receptor 5 (mGlu5)-positive allosteric modulators differentially induce or potentiate desensitization of mGlu5 signaling in recombinant cells and neurons
Hellyer, Shane D.
Albold, Sabine
Sengmany, Kathy
Singh, Junaid
Leach, Katie
Gregory, Karen J.
JOURNAL OF NEUROCHEMISTRY, 2019, 151 (03) : 301 - 315
[26] In vitro binding of a radio-labeled positive allosteric modulator for metabotropic glutamate receptor subtype 5
Zysk, John R.
Spear, Nathan
Fieles, William
Stein, Mark M.
Sygowski, Linda S.
King, Megan M.
Hoesch, Valerie
Hastings, Richard
Brockel, Becky
Do, Mylinh
Strom, Peter
Gadient, Reto
Chhajlani, Vijay
Elmore, Charles S.
Maier, Donna L.
SYNAPSE, 2013, 67 (03) : 135 - 144
[27] 4-(1-Phenyl-1H-pyrazol-4-yl)quinolines as novel, selective and brain penetrant metabotropic glutamate receptor 4 positive allosteric modulators
Jimenez, Hermogenes N.
Liu, Kevin G.
Hong, Sang-Phyo
Reitman, Michael S.
Uberti, Michelle A.
Bacolod, Maria D.
Cajina, Manuel
Nattini, Megan
Sabio, Michael
Doller, Dario
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (09) : 3235 - 3239
[28] N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement
Gregory, K. J.
Herman, E. J.
Ramsey, A. J.
Hammond, A. S.
Byun, N. E.
Stauffer, S. R.
Manka, J. T.
Jadhav, S.
Bridges, T. M.
Weaver, C. D.
Niswender, C. M.
Steckler, T.
Drinkenburg, W. H.
Ahnaou, A.
Lavreysen, H.
Macdonald, G. J.
Bartolome, J. M.
Mackie, C.
Hrupka, B. J.
Caron, M. G.
Daigle, T. L.
Lindsley, C. W.
Conn, P. J.
Jones, C. K.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2013, 347 (02): : 438 - 457
[29] Mechanisms Underlying Allosteric Molecular Switches of Metabotropic Glutamate Receptor 5
Llinas del Torrent, Claudia
Casajuana-Martin, Nil
Pardo, Leonardo
Tresadern, Gary
Perez-Benito, Laura
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2019, 59 (05) : 2456 - 2466
[30] Molecular determinants of positive allosteric modulation of the human metabotropic glutamate receptor 2
Farinha, A.
Lavreysen, H.
Peeters, L.
Russo, B.
Masure, S.
Trabanco, A. A.
Cid, J.
Tresadern, G.
BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (09) : 2383 - 2396

← 1 2 3 4 5 →