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)

• Published in: ACS chemical neuroscience 2016-09, Vol.7 (9), p.1192-1200
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Allosteric Regulation - drug effects; Amides - chemistry; Amides - pharmacology; Animals; Chromatography, High Pressure Liquid; Excitatory Amino Acid Agents - chemical synthesis; Excitatory Amino Acid Agents - chemistry; Excitatory Amino Acid Agents - pharmacology; Humans; Picolinic Acids - chemistry; Picolinic Acids - pharmacology; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Receptors, Metabotropic Glutamate - metabolism; Structure-Activity Relationship
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.6b00035

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.