title: Further optimization of the mGlu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound.
abstract: This Letter describes the progress and challenges in the continued optimization of the mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212. While many analogs addressed key areas for improvement, no one compound possessed the amalgamation of improvements needed within the (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanone scaffold to advance as a back-up clinical candidate. However, many analogs displayed excellent solubility and physiochemical properties, and were active in the amphetamine-induced hyperlocomotion (AHL) model. Moreover, the SAR was robust for this series of PAMs, and both polar and hydrogen-bond donors were found to be tolerated, leading to analogs with overall attractive profiles and good ligand efficiencies.
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Chrysa
authors.initials: C
authors.lastname: Malosh
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Conde-Ceide
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
authors.forename: Carlos Manuel
authors.initials: CM
authors.lastname: Martínez-Viturro
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Alcázar
authors.affiliation: Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Lavreysen
authors.affiliation: 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: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Gregor J
authors.initials: GJ
authors.lastname: Macdonald
authors.affiliation: Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain. Electronic address: jbartolo@its.jnj.com.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Bartolomé-Nebreda
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000494:Allosteric Regulation; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D064529:Receptor, Metabotropic Glutamate 5 / Q000737:chemistry / Q000627:therapeutic use*; D012559:Schizophrenia / Q000235:genetics*; D013329:Structure-Activity Relationship
chemical_list: D064529:Receptor, Metabotropic Glutamate 5
keywords: Metabotropic glutamate receptor; Pharmacokinetics; Positive allosteric modulator (PAM); Schizophrenia; mGlu(5)