Further exploration of an N-aryl phenoxyethoxy pyridinone-based series of mGlu3 NAMs: Challenging SAR, enantiospecific activity and in vivo efficacy
| Autor: | Kristen Gilliland, Anna L. Blobaum, Samantha E. Yohn, P. Jeffrey Conn, Craig W. Lindsley, Michael L. Schulte, Alice L. Rodriguez, Colleen M. Niswender, Mathew T. Loch, Yousuke Yamada |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Tail Suspension
010405 organic chemistry Stereochemistry Aryl Organic Chemistry Clinical Biochemistry Pharmaceutical Science Selective inhibition 01 natural sciences Biochemistry Zero maze 0104 chemical sciences Marble burying 010404 medicinal & biomolecular chemistry chemistry.chemical_compound chemistry In vivo Multidimensional optimization Drug Discovery Molecular Medicine G protein-coupled inwardly-rectifying potassium channel Molecular Biology |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 29:2670-2674 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2019.07.030 |
| Popis: | 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 (Ca2+ 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect