Further exploration of an N-aryl phenoxyethoxy pyridinone-based series of mGlu3 NAMs: Challenging SAR, enantiospecific activity and in vivo efficacy. Issue 18 (15th September 2019)

• Record Type: Journal Article
• Authors: Yamada, Yosuke; Yohn, Samantha E.; Gilliland, Kristen; Loch, Mathew T.; Schulte, Michael L.; Rodriguez, Alice L.; Blobaum, Anna L.; Niswender, Colleen M.; Conn, P. Jeffrey; Lindsley, Craig W.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 18(2019)
• Page Start: 2670
• Page End: 2674
• Publication Date: 2019-09-15
• Subjects: mGlu3 -- Metabotropic glutamate receptor -- Negative allosteric modulator (NAM) -- Structure-Activity Relationship (SAR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.07.030
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Detailed, multidimensional SAR around mGlu3 NAMs. Discovery of VU6017587, a new in vivo mGlu3 NAM tool compound. Selective inhibition of mGlu3 affords anxiolytic-like and antidepressant-like phenotypes in mice. Abstract: This letter describes the further optimization of a series of mGlu3 NAMs based on an N -aryl phenoxyethoxy pyridinone core. A multidimensional optimization campaign, with focused matrix libraries, quickly established challenging SAR, enantiospecific activity, differences in assay read-outs (Ca 2+ flux via a promiscuous G protein (Gα15 ) versus native coupling to GIRK channels), identified both full and partial mGlu3 NAMs and a new in vivo tool compound, VU6017587. This mGlu3 NAM showed efficacy in tail suspension, elevated zero maze and marble burying, suggesting selective inhibition of mGlu3 affords anxiolytic-like and antidepressant-like phenotypes in mice.