title: 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.
authors: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain. Electronic address: mlmartin@its.jnj.com.
authors: María Luz
authors: ML
authors: Martín-Martín
authors: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
authors: José Manuel
authors: JM
authors: Bartolomé-Nebreda
authors: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
authors: Susana
authors: S
authors: Conde-Ceide
authors: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
authors: Sergio A
authors: SA
authors: Alonso de Diego
authors: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
authors: Silvia
authors: S
authors: López
authors: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
authors: Carlos M
authors: CM
authors: Martínez-Viturro
authors: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
authors: Han Min
authors: HM
authors: Tong
authors: Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Hilde
authors: H
authors: Lavreysen
authors: Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Gregor J
authors: GJ
authors: Macdonald
authors: Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Thomas
authors: T
authors: Steckler
authors: Discovery Sciences ADME/Tox, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Claire
authors: C
authors: Mackie
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Thomas M
authors: TM
authors: Bridges
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: J Scott
authors: JS
authors: Daniels
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Colleen M
authors: CM
authors: Niswender
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Meredith J
authors: MJ
authors: Noetzel
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Carrie K
authors: CK
authors: Jones
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: P Jeffrey
authors: PJ
authors: Conn
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors: Craig W
authors: CW
authors: Lindsley
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors: Shaun R
authors: SR
authors: Stauffer
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008124:Locomotion / Q000187:drug effects; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D006574:Heterocyclic Compounds, 2-Ring; D007093:Imidazoles; D011744:Pyrimidinones; D064529:Receptor, Metabotropic Glutamate 5; C029899:imidazole
keywords: Dihydroimidazopyrimidinone; Imidazopyrimidinone; Metabotropic glutamate receptor 5 (mGlu(5)); Positive allosteric modulator (PAM); Schizophrenia