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)

Darren W. Engers, Anna L. Blobaum, Rocco D. Gogliotti, Yiu Yin Cheung, James M. Salovich, Pedro M. Garcia-Barrantes, J. Scott Daniels, Ryan Morrison, Carrie K. Jones, Matthew G. Soars, Xiaoliang Zhuo, Jeremy Hurley, John E. Macor, Joanne J. Bronson, P. Jeffrey Conn, Craig W. Lindsley, Colleen M. Niswender, Corey R. Hopkins

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The efficacy of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGlu4) in preclinical rodent models of Parkinson's disease has been established by a number of groups. Here, we report an advanced preclinically characterized mGlu4 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 mGlu4 PAM with suitable in vivo pharmacokinetic properties in three preclinical safety species.

Original languageEnglish (US)
Pages (from-to)1192-1200
Number of pages9
JournalACS Chemical Neuroscience
Volume7
Issue number9
DOIs
StatePublished - Sep 21 2016

Fingerprint

Modulators
Amines
Pharmacokinetics
Scaffolds
Amides
Parkinson Disease
Rodentia
Safety
metabotropic glutamate receptor 4
pyridine
picolinamide

Keywords

  • CYP induction
  • Metabotropic glutamate receptor 4
  • Parkinson's disease
  • mGlu
  • pyrazolo[4,3-b]pyridine

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

Cite this

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). / Engers, Darren W.; Blobaum, Anna L.; Gogliotti, Rocco D.; Cheung, Yiu Yin; Salovich, James M.; Garcia-Barrantes, Pedro M.; Daniels, J. Scott; Morrison, Ryan; Jones, Carrie K.; Soars, Matthew G.; Zhuo, Xiaoliang; Hurley, Jeremy; Macor, John E.; Bronson, Joanne J.; Conn, P. Jeffrey; Lindsley, Craig W.; Niswender, Colleen M.; Hopkins, Corey R.

In: ACS Chemical Neuroscience, Vol. 7, No. 9, 21.09.2016, p. 1192-1200.

Research output: Contribution to journalArticle

Engers, DW, Blobaum, AL, Gogliotti, RD, Cheung, YY, Salovich, JM, Garcia-Barrantes, PM, Daniels, JS, Morrison, R, Jones, CK, Soars, MG, Zhuo, X, Hurley, J, Macor, JE, Bronson, JJ, Conn, PJ, Lindsley, CW, Niswender, CM & Hopkins, CR 2016, '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)', ACS Chemical Neuroscience, vol. 7, no. 9, pp. 1192-1200. https://doi.org/10.1021/acschemneuro.6b00035
Engers, Darren W. ; Blobaum, Anna L. ; Gogliotti, Rocco D. ; Cheung, Yiu Yin ; Salovich, James M. ; Garcia-Barrantes, Pedro M. ; Daniels, J. Scott ; Morrison, Ryan ; Jones, Carrie K. ; Soars, Matthew G. ; Zhuo, Xiaoliang ; Hurley, Jeremy ; Macor, John E. ; Bronson, Joanne J. ; Conn, P. Jeffrey ; Lindsley, Craig W. ; Niswender, Colleen M. ; Hopkins, Corey R. / 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). In: ACS Chemical Neuroscience. 2016 ; Vol. 7, No. 9. pp. 1192-1200.
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