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] Positive allosteric modulators of metabotropic glutamate receptor 5: A new generation of antipsychotics?
Mutel, V
Bessis, AS
Epping-Jordan, M
Le Poul, E
Ludwig, B
Poli, SM
Rocher, JP
NEUROPSYCHOPHARMACOLOGY, 2005, 30 : S30 - S30
[2] Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5)
Varnes, Jeffrey G.
Marcus, Andrew P.
Mauger, Russell C.
Throner, Scott R.
Hoesch, Valerie
King, Megan M.
Wang, Xia
Sygowski, Linda A.
Spear, Nathan
Gadient, Reto
Brown, Dean G.
Campbell, James B.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (05) : 1402 - 1406
[3] Discovery of positive allosteric modulators of metabotropic glutamate receptor subtype 5 (mGluR5)
Williams, DL
Lindsley, CW
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2005, 5 (09) : 825 - 846
[4] 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
[5] Discovery of 1,5-Disubstituted Pyridones: A New Class of Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor
Maria Cid, Jose
Duvey, Guillaume
Cluzeau, Philippe
Nhem, Vanthea
Macary, Karim
Raux, Alexandre
Poirier, Nicolas
Muller, Jessica
Bolea, Christelle
Finn, Terry
Poli, Sonia
Epping-Jordan, Mark
Chamelot, Emilie
Derouet, Francis
Girard, Francoise
Macdonald, Gregor J.
Antonio Vega, Juan
Isabel de Lucas, Ana
Matesanz, Encarnacion
Lavreysen, Hilde
Lourdes Linares, Maria
Oehlrich, Daniel
Oyarzabal, Julen
Tresadern, Gary
Trabanco, Andres A.
Ignacio Andres, Jose
Le Poul, Emmanuel
Imogai, Hassan
Lutjens, Robert
Rocher, Jean-Philippe
ACS CHEMICAL NEUROSCIENCE, 2010, 1 (12): : 788 - 795
[6] A novel series of metabotropic glutamate receptor 5 negative allosteric modulators based on a 4,5,6,7-tetrahydropyrazolo [1,5-a]pyridine core
Duvey, Guillaume
Perry, Benjamin
Le Poul, Emmanuel
Poli, Sonia
Bonnet, Beatrice
Lambeng, Nathalie
Charvin, Delphine
Donovan-Rodrigues, Tansy
Haddouk, Hasnaa
Gagliardi, Stefania
Rocher, Jean-Philippe
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (16) : 4523 - 4527
[7] Allosteric Modulators of Metabotropic Glutamate Receptor 5 for Treatment of Schizophrenia
Conn, P. J.
Stauffer, S. R.
Zhou, S.
Manka, J.
Williams, R.
Noetzel, M. J.
Gregory, K. J.
Vinson, P.
Niswender, C. M.
Jones, C. K.
Steckler, T.
MacDonald, G.
Lindsley, C. W.
CURRENT NEUROPHARMACOLOGY, 2011, 9 : 11 - 12
[8] Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia
Fraley, Mark E.
EXPERT OPINION ON THERAPEUTIC PATENTS, 2009, 19 (09) : 1259 - 1275
[9] 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
[10] Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)
Stauffer, Shaun R.
ACS CHEMICAL NEUROSCIENCE, 2011, 2 (08): : 450 - 470

← 1 2 3 4 5 →