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
相关论文
共 50 条
  • [1] Discovery and characterization of N-(1,3-dialkyl-1 H-indazol-6-y1)-1H-pyrazolo [4,3-b] pyridin-3-amine scaffold as mGlu4 positive allosteric modulators that mitigate CYP1A2 induction liability
    Engers, Darren W.
    Bollinger, Sean R.
    Engers, Julie L.
    Panaresea, Joseph D.
    Breiner, Megan M.
    Gregro, Alison
    Blobaum, Anna L.
    Bronson, Joanne J.
    Wu, Yong-Jin
    Macor, John E.
    Rodriguez, Alice L.
    Zamorano, Rocio
    Conn, P. Jeffrey
    Lindsley, Craig W.
    Niswender, Colleen M.
    Hopkins, Corey R.
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2018, 28 (15) : 2641 - 2646
  • [2] 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)
    Bollinger, Sean R.
    Engers, Darren W.
    Panarese, Joseph D.
    West, Mary
    Engers, Julie L.
    Loch, Matthew T.
    Rodriguez, Alice L.
    Blobaum, Anna L.
    Jones, Carrie K.
    Gray, Analisa Thompson
    Conn, P. Jeffrey
    Lindsley, Craig W.
    Niswender, Colleen M.
    Hopkins, Corey R.
    JOURNAL OF MEDICINAL CHEMISTRY, 2019, 62 (01) : 342 - 358
  • [3] Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers
    Niswender, Colleen M.
    Jones, Carrie K.
    Lin, Xin
    Bubser, Michael
    Gray, Analisa Thompson
    Blobaum, Anna L.
    Engers, Darren W.
    Rodriguez, Alice L.
    Loch, Matthew T.
    Daniels, J. Scott
    Lindsley, Craig W.
    Hopkins, Corey R.
    Javitch, Jonathan A.
    Conn, P. Jeffrey
    ACS CHEMICAL NEUROSCIENCE, 2016, 7 (09): : 1201 - 1211
  • [4] Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4)
    Gogliotti, Rocco D.
    Blobaum, Anna L.
    Morrison, Ryan M.
    Daniels, J. Scott
    Salovich, James M.
    Cheung, Yiu-Yin
    Rodriguez, Alice L.
    Loch, Matthew T.
    Conn, P. Jeffrey
    Lindsley, Craig W.
    Niswender, Colleen M.
    Hopkins, Corey R.
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (13) : 2984 - 2987
  • [5] Synthesis and SAR of a novel metabotropic glutamate receptor 4 (mGlu4) antagonist: Unexpected 'molecular switch' from a closely related mGlu4 positive allosteric modulator
    Utley, Thomas
    Haddenham, Dustin
    Salovich, James M.
    Zamorano, Rocio
    Vinson, Paige N.
    Lindsley, Craig W.
    Hopkins, Corey R.
    Niswender, Colleen M.
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (23) : 6955 - 6959
  • [6] Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy
    Gogliotti, Rocco D.
    Engers, Darren W.
    Garcia-Barrantes, Pedro M.
    Panarese, Joseph D.
    Gentry, Patrick R.
    Blobaum, Anna L.
    Morrison, Ryan D.
    Daniels, J. Scott
    Thompson, Analisa D.
    Jones, Carrie K.
    Conn, P. Jeffrey
    Niswender, Colleen M.
    Lindsley, Craig W.
    Hopkins, Corey R.
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (12) : 2915 - 2919
  • [7] Discovery, Synthesis, and Structure-Activity Relationship Development of a Series of N-(4-Acetamido)phenylpicolinamides as Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4 (mGlu4) with CNS Exposure in Rats
    Engers, Darren W.
    Field, Julie R.
    Le, Uyen
    Zhou, Ya
    Bolinger, Julie D.
    Zamorano, Rocio
    Blobaum, Anna L.
    Jones, Carrie K.
    Jadhav, Satyawan
    Weaver, C. David
    Conn, P. Jeffrey
    Lindsley, Craig W.
    Niswender, Colleen M.
    Hopkins, Corey R.
    JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (04) : 1106 - 1110
  • [8] Discovery, Synthesis, and Structure-Activity Relationship Development of a Series of N-4-(2,5-Dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4) with Oral Efficacy in an Antiparkinsonian Animal Model
    Jones, Carrie K.
    Engers, Darren W.
    Thompson, Analisa D.
    Field, Julie R.
    Blobaum, Anna L.
    Lindsley, Stacey R.
    Zhou, Ya
    Gogliotti, Rocco D.
    Jadhav, Satyawan
    Zamorano, Rocio
    Bogenpohl, Jim
    Smith, Yoland
    Morrison, Ryan
    Daniels, J. Scott
    Weaver, C. David
    Conn, P. Jeffrey
    Lindsley, Craig W.
    Niswender, Colleen M.
    Hopkins, Corey R.
    JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (21) : 7639 - 7647
  • [9] 5,6-Dimethyl-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b] pyridin-3-amine
    Abdel-Aziz, Hatem A.
    Al-Rashood, Khalid A.
    Ghabbour, Hazem A.
    Chantrapromma, Suchada
    Fun, Hoong-Kun
    ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2012, 68 : O612 - U1479
  • [10] Synthesis and Docking studies of 1-Phenyl-3-(4-(pyridin-2-ylmethyl) piperazin-1-yl)-1H-pyrazolo[4,3-b]pyridine
    Srivani, K.
    Laxminarayana, E.
    Ramchander, M.
    Chary, M. Thirumala
    INDIAN JOURNAL OF HETEROCYCLIC CHEMISTRY, 2019, 29 (03) : 233 - 237
12345