title: Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel alpha 7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models.
abstract: A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA. christopher.j.odonnell@pfizer.com
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Rogers
authors.forename: Brian S
authors.initials: BS
authors.lastname: Bronk
authors.forename: Dianne K
authors.initials: DK
authors.lastname: Bryce
authors.forename: Jotham W
authors.initials: JW
authors.lastname: Coe
authors.forename: Karen K
authors.initials: KK
authors.lastname: Cook
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Duplantier
authors.forename: Edelweiss
authors.initials: E
authors.lastname: Evrard
authors.forename: Mihaly
authors.initials: M
authors.lastname: Hajós
authors.forename: William E
authors.initials: WE
authors.lastname: Hoffmann
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Hurst
authors.forename: Noha
authors.initials: N
authors.lastname: Maklad
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mather
authors.forename: Stafford
authors.initials: S
authors.lastname: McLean
authors.forename: Frank M
authors.initials: FM
authors.lastname: Nedza
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
authors.forename: Langu
authors.initials: L
authors.lastname: Peng
authors.forename: Weimin
authors.initials: W
authors.lastname: Qian
authors.forename: Melinda M
authors.initials: MM
authors.lastname: Rottas
authors.forename: Steven B
authors.initials: SB
authors.lastname: Sands
authors.forename: Anne W
authors.initials: AW
authors.lastname: Schmidt
authors.forename: Alka V
authors.initials: AV
authors.lastname: Shrikhande
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Spracklin
authors.forename: Diane F
authors.initials: DF
authors.lastname: Wong
authors.forename: Andy
authors.initials: A
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000188:drug therapy*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry*; D012559:Schizophrenia / Q000188:drug therapy*; D012867:Skin / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D014982:Xenopus laevis / Q000254:growth & development; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C547674:4-(5-methyloxazolo(4,5-b)pyridin-2-yl)-1,4-diazabicyclo(3.2.2)nonane; D053961:Azabicyclo Compounds; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D010080:Oxazoles; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor