Abstract |
We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.
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Authors | María Luz Martín-Martín, José Manuel Bartolomé-Nebreda, Susana Conde-Ceide, Sergio A Alonso de Diego, Silvia López, Carlos M Martínez-Viturro, Han Min Tong, Hilde Lavreysen, Gregor J Macdonald, Thomas Steckler, Claire Mackie, Thomas M Bridges, J Scott Daniels, Colleen M Niswender, Meredith J Noetzel, Carrie K Jones, P Jeffrey Conn, Craig W Lindsley, Shaun R Stauffer |
Journal | Bioorganic & medicinal chemistry letters
(Bioorg Med Chem Lett)
Vol. 25
Issue 6
Pg. 1310-7
(Mar 15 2015)
ISSN: 1464-3405 [Electronic] England |
PMID | 25683622
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2015 Elsevier Ltd. All rights reserved. |
Chemical References |
- Antipsychotic Agents
- Heterocyclic Compounds, 2-Ring
- Imidazoles
- Pyrimidinones
- Receptor, Metabotropic Glutamate 5
- imidazole
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Topics |
- Allosteric Regulation
- Animals
- Antipsychotic Agents
(chemical synthesis, chemistry, pharmacokinetics)
- Brain
(metabolism)
- Drug Evaluation, Preclinical
- Half-Life
- Heterocyclic Compounds, 2-Ring
(chemical synthesis, chemistry, pharmacokinetics)
- Humans
- Imidazoles
(chemical synthesis, chemistry, pharmacokinetics)
- Locomotion
(drug effects)
- Microsomes, Liver
(metabolism)
- Protein Binding
- Pyrimidinones
(chemical synthesis, chemistry, pharmacokinetics)
- Rats
- Receptor, Metabotropic Glutamate 5
(chemistry, metabolism)
- Structure-Activity Relationship
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