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
收藏
页码：1192 / 1200
页数：9
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