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 language | English (US) |
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Pages (from-to) | 1192-1200 |
Number of pages | 9 |
Journal | ACS Chemical Neuroscience |
Volume | 7 |
Issue number | 9 |
DOIs | |
State | Published - Sep 21 2016 |
Externally published | Yes |
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