Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4)

被引：38

作者：

Engers, Darren W. ^{[1
,3
]}

Blobaum, Anna L. ^{[1
,3
]}

Gogliotti, Rocco D. ^{[1
,3
]}

Cheung, Yiu-Yin ^{[1
,3
]}

Salovich, James M. ^{[1
,3
]}

Garcia-Barrantes, Pedro M. ^{[3
]}

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

Morrison, Ryan ^{[1
,3
]}

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

Soars, Matthew G. ^{[5
]}

Zhuo, Xiaoliang ^{[5
]}

Hurley, Jeremy ^{[5
]}

Macor, John E. ^{[5
]}

Bronson, Joanne J. ^{[5
]}

Conn, P. Jeffrey ^{[1
,3
,4
]}

Lindsley, Craig W. ^{[1
,2
,3
]}

Niswender, Colleen M. ^{[1
,3
,4
]}

Hopkins, Corey R. ^{[1
,2
,3
]}

机构：

[1] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

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

[4] Vanderbilt Univ, Vanderbilt Kennedy Ctr, Nashville, TN 37232 USA

[5] Bristol Myers Squibb Co, Res & Dev, 5 Res Pkwy, Wallingford, CT 06492 USA

来源：

ACS CHEMICAL NEUROSCIENCE | 2016年 / 7卷 / 09期

关键词：

Metabotropic glutamate receptor 4; mGlu(4); CYP induction; Parkinson's disease; pyrazolo[4,3-b]pyridine; RECENT PROGRESS; L-DOPA; PARKINSONS; BINDING; CLEARANCE; EFFICACY; PLASMA; SERIES; BRAIN;

D O I：

10.1021/acschemneuro.6b00035

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The efficacy of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGlu(4)) in preclinical rodent models of Parkinson's disease has been established by a number of groups. Here, we report an advanced preclinically characterized mGlu(4) PAM, N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506). We detail the discovery of VU0418506 starting from a common picolinamide core scaffold and evaluation of a number of amide bioisosteres leading to the novel pyrazolo[4,3-b]pyridine head group. VU0418506 has been characterized as a potent and selective mGlu(4) PAM with suitable in vivo pharmacokinetic properties in three preclinical safety species.

引用

页码：1192 / 1200

页数：9

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