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

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...

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Bibliographic Details
Published inBioorganic & 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
LanguageEnglish
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
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Summary: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 the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
ISSN:1464-3405