title: Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia.
abstract: Herein, we report the structure-activity relationship of a novel series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected as a candidate for further development.
authors.affiliation: Neuroscience Medicinal Chemistry and Discovery Sciences Lead Discovery, Janssen Research and Development , Jarama 75A, 45007 Toledo, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Conde-Ceide
authors.affiliation: Neuroscience Medicinal Chemistry and Discovery Sciences Lead Discovery, Janssen Research and Development , Jarama 75A, 45007 Toledo, Spain.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Martínez-Viturro
authors.affiliation: Neuroscience Medicinal Chemistry and Discovery Sciences Lead Discovery, Janssen Research and Development , Jarama 75A, 45007 Toledo, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Alcázar
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Garcia-Barrantes
authors.affiliation: Neuroscience and Discovery Sciences ADME/Tox, Janssen Research and Development , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Lavreysen
authors.affiliation: Neuroscience and Discovery Sciences ADME/Tox, Janssen Research and Development , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Claire
authors.initials: C
authors.lastname: Mackie
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Paige N
authors.initials: PN
authors.lastname: Vinson
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Jerri M
authors.initials: JM
authors.lastname: Rook
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.affiliation: Neuroscience and Discovery Sciences ADME/Tox, Janssen Research and Development , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Anton
authors.initials: A
authors.lastname: Megens
authors.affiliation: Neuroscience and Discovery Sciences ADME/Tox, Janssen Research and Development , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.affiliation: Neuroscience and Discovery Sciences ADME/Tox, Janssen Research and Development , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Wilhelmus H
authors.initials: WH
authors.lastname: Drinkenburg
authors.affiliation: Neuroscience and Discovery Sciences ADME/Tox, Janssen Research and Development , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Abdellah
authors.initials: A
authors.lastname: Ahnaou
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: Neuroscience and Discovery Sciences ADME/Tox, Janssen Research and Development , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Gregor J
authors.initials: GJ
authors.lastname: Macdonald
authors.affiliation: Neuroscience and Discovery Sciences ADME/Tox, Janssen Research and Development , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.affiliation: Neuroscience Medicinal Chemistry and Discovery Sciences Lead Discovery, Janssen Research and Development , Jarama 75A, 45007 Toledo, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Bartolomé-Nebreda
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
keywords: 4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine; JNJ-46778212; Positive allosteric modulator (PAM); VU0409551; metabotropic glutamate receptor 5 (mGlu5); schizophrenia