title: Discovery of VU0467485/AZ13713945: An M4PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia.
abstract: Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs). Compound6c(VU0467485) possesses robustin vitroM4PAM potency across species andin vivoefficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK,6c(VU0467485) was evaluated as a preclinical development candidate.
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Noetzel
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Melancon
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Poslusney
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
authors.forename: Kellie D
authors.initials: KD
authors.lastname: Nance
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Hurtado
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Vincent B
authors.initials: VB
authors.lastname: Luscombe
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Weiner
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Atin
authors.initials: A
authors.lastname: Lamsal
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Sichen
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Bubser
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: AstraZeneca Neuroscience , Innovative Medicines Biotech Unit, 141 Portland Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: AstraZeneca Neuroscience , Innovative Medicines Biotech Unit, 141 Portland Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Wood
authors.affiliation: AstraZeneca Neuroscience , Innovative Medicines Biotech Unit, 141 Portland Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
keywords: Positive allosteric modulator (PAM); VU0467485; muscarinic acetylcholine receptor 4 (M4); schizophrenia