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

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22 Scopus citations

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.

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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

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