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

Autor:	Carlos M. Martínez-Viturro, Colleen M. Niswender, Han Min Tong, Meredith J. Noetzel, Gregor James Macdonald, Susana Conde-Ceide, Carrie K. Jones, Claire Mackie, José Manuel Bartolomé-Nebreda, Thomas Steckler, P. Jeffrey Conn, Shaun R. Stauffer, Craig W. Lindsley, María Luz Martín-Martín, Thomas M. Bridges, J. Scott Daniels, Hilde Lavreysen, Silvia López, Sergio A. Alonso de Diego
Rok vydání:	2015
Předmět:	Receptor Metabotropic Glutamate 5 Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Pyrimidinones Pharmacology Heterocyclic Compounds 2-Ring Biochemistry Article Structure-Activity Relationship Allosteric Regulation Drug Discovery Animals Humans Molecular Biology Metabotropic glutamate receptor 8 Chemistry Metabotropic glutamate receptor 5 Metabotropic glutamate receptor 4 Organic Chemistry Metabotropic glutamate receptor 7 Imidazoles Metabotropic glutamate receptor 6 Brain Rats Microsomes Liver Molecular Medicine Metabotropic glutamate receptor 1 Metabotropic glutamate receptor 3 Metabotropic glutamate receptor 2 Locomotion Antipsychotic Agents Half-Life Protein Binding
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 25:1310-1317
ISSN:	0960-894X
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e4a364a4c4741589a3db21524a2a658a https://doi.org/10.1016/j.bmcl.2015.01.038 Zobrazit plný text záznamu Full Text from ScienceDirect