title: Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationship.
abstract: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.
authors.affiliation: Pfizer Global Research & Development, Eastern Point Road, Groton, Connecticut 06340, USA.
authors.forename: Donn G
authors.initials: DG
authors.lastname: Wishka
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Walker
authors.forename: Karen M
authors.initials: KM
authors.lastname: Yates
authors.forename: Steven C
authors.initials: SC
authors.lastname: Reitz
authors.forename: Shaojuan
authors.initials: S
authors.lastname: Jia
authors.forename: Jason K
authors.initials: JK
authors.lastname: Myers
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Olson
authors.forename: E Jon
authors.initials: EJ
authors.lastname: Jacobsen
authors.forename: Mark L
authors.initials: ML
authors.lastname: Wolfe
authors.forename: Vincent E
authors.initials: VE
authors.lastname: Groppi
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Hanchar
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Thornburgh
authors.forename: Luz A
authors.initials: LA
authors.lastname: Cortes-Burgos
authors.forename: Erik H F
authors.initials: EH
authors.lastname: Wong
authors.forename: Brian A
authors.initials: BA
authors.lastname: Staton
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Raub
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Higdon
authors.forename: Theron M
authors.initials: TM
authors.lastname: Wall
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Hurst
authors.forename: Rodney R
authors.initials: RR
authors.lastname: Walters
authors.forename: William E
authors.initials: WE
authors.lastname: Hoffmann
authors.forename: Mihaly
authors.initials: M
authors.lastname: Hajos
authors.forename: Stanley
authors.initials: S
authors.lastname: Franklin
authors.forename: Galen
authors.initials: G
authors.lastname: Carey
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Gold
authors.forename: Karen K
authors.initials: KK
authors.lastname: Cook
authors.forename: Steven B
authors.initials: SB
authors.lastname: Sands
authors.forename: Sabrina X
authors.initials: SX
authors.lastname: Zhao
authors.forename: John R
authors.initials: JR
authors.lastname: Soglia
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Arneric
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Rogers
mesh_terms: D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy*; D004355:Drug Stability; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism* / Q000502:physiology; D021641:Recognition, Psychology / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D051638:Ether-A-Go-Go Potassium Channels; C513163:N-(1-azabicyclo(2.2.2)oct-3-yl)furo(2,3-c)pyridine-5-carboxamide; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor