Preliminary investigation of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives as a novel series of mGlu5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia

被引：7

作者：

Conde-Ceide, Susana ^{[1
]}

Alcazar, Jesus ^{[1
]}

Alonso de Diego, Sergio A. ^{[1
]}

Lopez, Silvia ^{[1
]}

Luz Martin-Martin, Maria ^{[1
]}

Martinez-Viturro, Carlos M. ^{[1
]}

Pena, Miguel-Angel ^{[1
]}

Min Tong, Han ^{[1
]}

Lavreysen, Hilde ^{[2
]}

Mackie, Claire ^{[3
]}

Bridges, Thomas M. ^{[4
,5
]}

Daniels, J. Scott ^{[4
,5
]}

Niswender, Colleen M. ^{[4
,5
]}

Jones, Carrie K. ^{[4
,5
]}

Macdonald, Gregor J. ^{[2
]}

Steckler, Thomas ^{[2
]}

Conn, P. Jeffrey ^{[4
,5
]}

Stauffer, Shaun R. ^{[4
,5
]}

Lindsley, Craig W. ^{[4
,5
]}

Manuel Bartolome-Nebreda, Jose ^{[1
]}

机构：

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

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

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

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

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 02期

关键词：

Metabotropic glutamate receptor; mGlu(5); N-Methyl-D-aspartate (NMDA); Positive allosteric modulator (PAM); Schizophrenia; NMDA; VU0409551/JNJ-46778212; HYPOFUNCTION; LSN2463359; DISCOVERY; FAMILY; MOTOR;

D O I：

10.1016/j.bmcl.2015.11.098

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu(5) positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu(5) PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu(5) activation and target-related toxicities. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：429 / 434

页数：6

共 10 条

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[2] Synthesis, structure characterization and preliminary biological evaluation of novel 5-alkyl-2-ferrocenyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives
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Shin, Dong-Soo
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[3] 2-(4-Chlorophenyl)-5-(3,4-dimethoxyphenethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
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[4] 5-Alkyl-2-ferrocenyl-6,7-dihydropyrazolo[1,5-a] pyrazin-4(5H)-one derivatives inhibit growth of lung cancer A549 cell by inducing apoptosis
Pan, Xiao-Hong
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Xie, Yong-Sheng
Shin, Dong-Soo
Zhang, Shang-Li
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[5] Identification of (6S)-cyclopropyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamines as new HBV capsid assembly modulators
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Wu, Shuo
Tao, Zeyu
Wang, Aoyu
Xu, Shijie
Yang, Lu
Gao, Qiang
Wang, Apeng
Qin, Xiaoyu
Jiang, Bin
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Jiang, Jiandong
Liu, Mingliang
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[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
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[7] Synthesis, single-crystal characterization and preliminary biological evaluation of novel ferrocenyl pyrazolo[1,5-a]pyrazin-4(5H)-one derivatives
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Zhao, Hong-Ling
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Liu, Jin-Ting
Li, Ji-Kun
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2010, 45 (01) : 210 - 218
[8] Microwave-assisted rapid and straightforward synthesis of novel 6-(aroxymethyl)-2-aryl-6,7-dihydropyrazolo[5,1-c][1,4]oxazin-4-one derivatives
Wei, Fang
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Dong, Wen-Liang
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[9] Synthesis and preliminary biological evaluation of novel pyrazolo[1,5-a] pyrazin-4(5H)-one derivatives as potential agents against A549 lung cancer cells
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[10] Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1H-Pyrazolo[4,3-b]pyridin-3-yl)amino)-benzo[d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu4)
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Loch, Matthew T.
Rodriguez, Alice L.
Blobaum, Anna L.
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