The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu 4 PAM development candidate

• Published in: Bioorganic & medicinal chemistry letters Vol. 29; no. 2; p. 342
• Main Authors: Panarese, Joseph D, Engers, Darren W, Wu, Yong-Jin, Guernon, Jason M, Chun, Aspen, Gregro, Alison R, Bender, Aaron M, Capstick, Rory A, Wieting, Joshua M, Bronson, Joanne J, Macor, John E, Westphal, Ryan, Soars, Matthew, Engers, Julie E, Felts, Andrew S, Rodriguez, Alice L, Emmitte, Kyle A, Jones, Carrie K, Blobaum, Anna L, Conn, P Jeffrey, Niswender, Colleen M, Hopkins, Corey R, Lindsley, Craig W
• Format: Journal Article
• Language: English
• Published: England 15.01.2019
• Subjects: Allosteric Regulation - drug effects; Dose-Response Relationship, Drug; Drug Discovery; Heterocyclic Compounds, 2-Ring - chemistry; Heterocyclic Compounds, 2-Ring - pharmacology; Humans; Isoquinolines - chemistry; Isoquinolines - pharmacology; Molecular Structure; Myotonin-Protein Kinase - antagonists & inhibitors; Myotonin-Protein Kinase - metabolism; Receptors, Metabotropic Glutamate - metabolism; Structure-Activity Relationship; mGlu; Structure-activity relationship (SAR); Positive allosteric modulator (PAM); Parkinson’s disease (PD); Metabotropic glutamate receptor

This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail th...