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Discovery and SAR of novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).

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.
AuthorsMaría 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
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 6 Pg. 1310-7 (Mar 15 2015) ISSN: 1464-3405 [Electronic] England
PMID25683622 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2015 Elsevier Ltd. All rights reserved.
Chemical References
  • Antipsychotic Agents
  • Heterocyclic Compounds, 2-Ring
  • Imidazoles
  • Pyrimidinones
  • Receptor, Metabotropic Glutamate 5
  • imidazole
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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