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 Chem Neurosci. 2016 Sep 21;7(9):1192-200. doi: 10.1021/acschemneuro.6b00035.
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  1 ,  Xiaoliang Zhuo  1 ,  Jeremy Hurley  1 ,  John E Macor  1 ,  Joanne J Bronson  1 ,  P Jeffrey Conn ,  Craig W Lindsley ,  Colleen M Niswender ,  Corey R Hopkins
Affiliations
  • 1. Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
PMID: 27075300 DOI: 10.1021/acschemneuro.6b00035
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.

Keywords
CYP induction; Metabotropic glutamate receptor 4; Parkinson’s disease; mGlu4; pyrazolo[4,3-b]pyridine.
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