ArticleBioorganic & medicinal chemistry letters2014
Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency.
Article in Bioorganic & medicinal chemistry letters, 2014. 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.
- Allosteric Molecular Switches in Metabotropic Glutamate Receptors.ChemMedChem · 2021Review
- Preliminary investigation of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives as a novel series of mGlu5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia.Bioorganic & medicinal chemistry letters · 2016Article
- The Role of mGlu Receptors in Hippocampal Plasticity Deficits in Neurological and Psychiatric Disorders: Implications for Allosteric Modulators as Novel Therapeutic Strategies.Current neuropharmacology · 2016Review
- Acyl dihydropyrazolo[1,5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators.Bioorganic & medicinal chemistry letters · 2015Article
- Further optimization of the mGlu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound.Bioorganic & medicinal chemistry letters · 2015Article
- The twin drug approach for novel nicotinic acetylcholine receptor ligands.Bioorganic & medicinal chemistry · 2015Article
- Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation.Molecular pharmacology · 2015Article
Corrections and comments
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Authors and funding
17 authors.
Funding
Abstract
We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (11, VU0462054), bearing a simple ketone moiety, was identified (LE=0.52, LELP=3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series.
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