title: 2,6-Disubstituted pyrazines and related analogs as NR2B site antagonists of the NMDA receptor with anti-depressant activity.
abstract: Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good potency, but also presented a hERG liability. Further modifications led to examples of non-basic replacements which demonstrated much less liability in this regard. Finally, one compound in the series, 6a, was tested in the mouse forced swim depression assay and found to show activity (s.c. 60 mg/kg).
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850-5437, USA. dean.brown@astrazeneca.com
authors.forename: Dean G
authors.initials: DG
authors.lastname: Brown
authors.forename: Donna L
authors.initials: DL
authors.lastname: Maier
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sylvester
authors.forename: Tiffany N
authors.initials: TN
authors.lastname: Hoerter
authors.forename: Elnaz
authors.initials: E
authors.lastname: Menhaji-Klotz
authors.forename: Celina C
authors.initials: CC
authors.lastname: Lasota
authors.forename: Lee T
authors.initials: LT
authors.lastname: Hirata
authors.forename: Deidre E
authors.initials: DE
authors.lastname: Wilkins
authors.forename: Clay W
authors.initials: CW
authors.lastname: Scott
authors.forename: Shephali
authors.initials: S
authors.lastname: Trivedi
authors.forename: Tongming
authors.initials: T
authors.lastname: Chen
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: McCarthy
authors.forename: Carla M
authors.initials: CM
authors.lastname: Maciag
authors.forename: Evelynjeane J
authors.initials: EJ
authors.lastname: Sutton
authors.forename: Jerry
authors.initials: J
authors.lastname: Cumberledge
authors.forename: Don
authors.initials: D
authors.lastname: Mathisen
authors.forename: John
authors.initials: J
authors.lastname: Roberts
authors.forename: Anshul
authors.initials: A
authors.lastname: Gupta
authors.forename: Frank
authors.initials: F
authors.lastname: Liu
authors.forename: Charles S
authors.initials: CS
authors.lastname: Elmore
authors.forename: Cristobal
authors.initials: C
authors.lastname: Alhambra
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Krumrine
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Ciaccio
authors.forename: Michael W
authors.initials: MW
authors.lastname: Wood
authors.forename: James B
authors.initials: JB
authors.lastname: Campbell
authors.forename: Magnus J
authors.initials: MJ
authors.lastname: Johansson
authors.forename: Jian
authors.initials: J
authors.lastname: Xia
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Wen
authors.forename: Ji
authors.initials: J
authors.lastname: Jiang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.forename: Zuozhong
authors.initials: Z
authors.lastname: Peng
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D000928:Antidepressive Agents; C121001:NR2B NMDA receptor; D011719:Pyrazines; D016194:Receptors, N-Methyl-D-Aspartate