title: N-Acyl-N'-arylpiperazines as negative allosteric modulators of mGlu1: identification of VU0469650, a potent and selective tool compound with CNS exposure in rats.
abstract: Development of SAR in an N-acyl-N'-arylpiperazine series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. Characterization of selected compounds in protein binding assays was used to aid in selecting VU0469650 for further profiling in ancillary pharmacology assays and pharmacokinetic studies. VU0469650 demonstrated an excellent selectivity profile and good exposure in both plasma and brain samples following intraperitoneal dosing in rats.
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Lovell
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Felts
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.forename: Daryl F
authors.initials: DF
authors.lastname: Venable
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morrison
authors.forename: Frank W
authors.initials: FW
authors.lastname: Byers
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Emmitte
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010879:Piperazines; D018094:Receptors, Metabotropic Glutamate; C585538:VU0469650; C104077:metabotropic glutamate receptor type 1