title: 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts.
abstract: Hit to lead optimization of (5R)-5-hexyl-3-phenyl-1,3-oxazolidin-2-one as a positive allosteric modulator of mGluR2 is described. Improvements in potency and metabolic stability were achieved through SAR on both ends of the oxazolidinone. An optimized lead compound was found to be brain penetrant and active in a rat ketamine-induced hyperlocomotion model for antipsychotic activity.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. edward_brnardic@merck.com
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Brnardic
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.forename: Mark E
authors.initials: ME
authors.lastname: Layton
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Chris
authors.initials: C
authors.lastname: Culberson
authors.forename: Marlene A
authors.initials: MA
authors.lastname: Jacobson
authors.forename: Brian C
authors.initials: BC
authors.lastname: Magliaro
authors.forename: Pete H
authors.initials: PH
authors.lastname: Hutson
authors.forename: Julie A
authors.initials: JA
authors.lastname: O'Brien
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Huszar
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Fillgrove
authors.forename: Cuyue
authors.initials: C
authors.lastname: Tang
authors.forename: Yuhsin
authors.initials: Y
authors.lastname: Kuo
authors.forename: Sylvie M
authors.initials: SM
authors.lastname: Sur
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D014150:Antipsychotic Agents; D007649:Ketamine / Q000633:toxicity; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D023303:Oxazolidinones; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D007649:Ketamine