ArticleBioorganic & medicinal chemistry letters2015
Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 1: SAR of modifications to the central aryl core.
Article in Bioorganic & medicinal chemistry letters, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Further Optimization of the mGluACS chemical neuroscience · 2025Article
- Discovery of VU6024578/BI02982816: An mGluJournal of medicinal chemistry · 2024Article
- Photoswitchable positive allosteric modulators of metabotropic glutamate receptor 4 to improve selectivity.iScience · 2024Article
- Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease.Pharmacological reviews · 2022Review
- Discovery of new GPCR ligands to illuminate new biology.Nature chemical biology · 2017Article
- Targeting metabotropic glutamate receptors for novel treatments of schizophrenia.Molecular brain · 2017Review
- Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.Chemical reviews · 2016Review
- Re-exploration of the mGlu₁ PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR.Bioorganic & medicinal chemistry letters · 2016Article
- Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 3. Engineering plasma stability by discovery and optimization of isoindolinone analogs.Bioorganic & medicinal chemistry letters · 2016Article
- Lead optimization of the VU0486321 series of mGlu(1) PAMs. Part 2: SAR of alternative 3-methyl heterocycles and progress towards an in vivo tool.Bioorganic & medicinal chemistry letters · 2016Article
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6 authors.
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Abstract
This Letter describes the lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs). While first generation PAMs from Roche were reported in the late 1990s, little effort has focused on the development of mGlu1 PAMs since. New genetic data linking loss-of-function mutant mGlu1 receptors to schizophrenia, bipolar disorder and other neuropsychiatric disorders has rekindled interest in the target, but the ideal in vivo probe, for example, with good PK, brain penetration and low plasma protein binding, for robust target validation has been lacking. Here we describe the first modifications to the central aryl core of the VU0486321 series, where robust SAR was noted. Moreover, structural variants were identified that imparted selectivity (up to >793-fold) versus mGlu4.
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