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

Martín-Martín ML, Bartolomé-Nebreda JM, Conde-Ceide S, Alonso de Diego SA, López S, Martínez-Viturro CM, Tong HM, Lavreysen H, Macdonald GJ, Steckler T, Mackie C, Bridges TM, Daniels JS, Niswender CM, Noetzel MJ, Jones CK, Conn PJ, Lindsley CW, Stauffer SR
Bioorg Med Chem Lett. 2015 25 (6): 1310-7

PMID: 25683622 · PMCID: PMC4399811 · DOI:10.1016/j.bmcl.2015.01.038

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.

Copyright © 2015 Elsevier Ltd. All rights reserved.

MeSH Terms (16)

Allosteric Regulation Animals Antipsychotic Agents Brain Drug Evaluation, Preclinical Half-Life Heterocyclic Compounds, 2-Ring Humans Imidazoles Locomotion Microsomes, Liver Protein Binding Pyrimidinones Rats Receptor, Metabotropic Glutamate 5 Structure-Activity Relationship

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