ArticleBioorganic & medicinal chemistry letters2016
Re-exploration of the mGlu₁ PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR.
Article in Bioorganic & medicinal chemistry letters, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Further Optimization of the mGluACS chemical neuroscience · 2025Article
- Discovery of VU6024578/BI02982816: An mGluJournal of medicinal chemistry · 2024Article
- Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease.Pharmacological reviews · 2022Review
- Allosteric Molecular Switches in Metabotropic Glutamate Receptors.ChemMedChem · 2021Review
- Activation of the mGluMolecular psychiatry · 2020Article
- Shared Behavioral and Neurocircuitry Disruptions in Drug Addiction, Obesity, and Binge Eating Disorder: Focus on Group I mGluRs in the Mesolimbic Dopamine Pathway.ACS chemical neuroscience · 2019Review
- Targeting metabotropic glutamate receptors for novel treatments of schizophrenia.Molecular brain · 2017Review
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
This letter describes the re-exploration of the mGlu1 PAM Ro 07-11401 scaffold through a multi-dimensional, iterative parallel synthesis approach. Unlike recent series of mGlu1 PAMs with robust SAR, the SAR around the Ro 07-11401 structure was incredibly steep (only ∼6 of 200 analogs displayed mGlu1 PAM activity), and reminiscent of the CPPHA mGlu5 PAM scaffold. Despite the steep SAR, two new thiazole derivatives were discovered with improved in vitro DMPK profiles and ∼3- to 4-fold improvement in CNS exposure (Kps 1.01-1.19); albeit, with a ∼3-fold diminution in mGlu1 PAM potency, yet comparable efficacy (∼5-fold leftward shift of the glutamate concentration-response curve at 10μM). Thus, this effort has provided additional CNS penetrant mGlu1 PAM tools in a different chemotype than the VU0486321 scaffold. These compounds will permit a better understanding of the pharmacology and therapeutic potential of selective mGlu1 activation, while highlighting the steep SAR challenges that can often be encountered in GPCR allosteric modulator discovery.
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Registered trials
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