2. Academic Validation
  3. 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)

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

Affiliation

  • 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.

Figures
Products