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)
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.
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.
p. 1192 - 1200
(2016/10/03)
PYRAZOLOPYRIDINE, PYRAZOLOPYRAZINE, PYRAZOLOPYRIMIDINE, PYRAZOLOTHIOPHENE AND PYRAZOLOTHIAZOLE COMPOUNDS AS MGLUR4 ALLOSTERIC POTENTIATORS, COMPOUNDS, AND METHODS OF TREATING NEUROLOGICAL DYSFUNCTION
Pyrazolopyridine, pyrazolopyrazine, pyrazolopyrimidine, pyrazolothiophene and pyrazolothiazole compounds which are useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of using the compounds, for example, in treating neurological and psychiatric disorders or other disease state associated with glutamate dysfunction.
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(2011/09/15)
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