title: Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists.
abstract: A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.
authors.affiliation: Neuroscience Research, Pfizer Global Research and Development, Eastern Point Rd., Groton, CT 06340, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Walker
authors.forename: Donn G
authors.initials: DG
authors.lastname: Wishka
authors.forename: David W
authors.initials: DW
authors.lastname: Piotrowski
authors.forename: Shaojuan
authors.initials: S
authors.lastname: Jia
authors.forename: Steven C
authors.initials: SC
authors.lastname: Reitz
authors.forename: Karen M
authors.initials: KM
authors.lastname: Yates
authors.forename: Jason K
authors.initials: JK
authors.lastname: Myers
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Vetman
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Margolis
authors.forename: E Jon
authors.initials: EJ
authors.lastname: Jacobsen
authors.forename: Brad A
authors.initials: BA
authors.lastname: Acker
authors.forename: Vincent E
authors.initials: VE
authors.lastname: Groppi
authors.forename: Mark L
authors.initials: ML
authors.lastname: Wolfe
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Thornburgh
authors.forename: Paula M
authors.initials: PM
authors.lastname: Tinholt
authors.forename: Luz A
authors.initials: LA
authors.lastname: Cortes-Burgos
authors.forename: Rodney R
authors.initials: RR
authors.lastname: Walters
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hester
authors.forename: Eric P
authors.initials: EP
authors.lastname: Seest
authors.forename: Lester A
authors.initials: LA
authors.lastname: Dolak
authors.forename: Fusen
authors.initials: F
authors.lastname: Han
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Olson
authors.forename: Laura
authors.initials: L
authors.lastname: Fitzgerald
authors.forename: Brian A
authors.initials: BA
authors.lastname: Staton
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Raub
authors.forename: Mihaly
authors.initials: M
authors.lastname: Hajos
authors.forename: William E
authors.initials: WE
authors.lastname: Hoffmann
authors.forename: Kai S
authors.initials: KS
authors.lastname: Li
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: Erik H F
authors.initials: EH
authors.lastname: Wong
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Rogers
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002038:Bungarotoxins; D002478:Cells, Cultured; D015195:Drug Design; D004594:Electrophysiology; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D002038:Bungarotoxins; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor