title: The discovery of 2-fluoro-N-(3-fluoro-4-(5-((4-morpholinobutyl)amino)-1,3,4-oxadiazol-2-yl)phenyl)benzamide, a full agonist of the alpha-7 nicotinic acetylcholine receptor showing efficacy in the novel object recognition model of cognition enhancement.
abstract: A series of α7 nicotinic acetylcholine receptor full agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Early lead 1 was found to have a limited therapeutic index with respect to its potential for cardiovascular side effects. Further optimisation of this series led to the identification of 22 a potent full agonist showing efficacy at a dose of 0.1mg/kg in the novel object recognition model of cognition enhancement. Comparison of 1 with 22 demonstrated the latter to have an improved oral pharmacokinetic profile and cardiovascular therapeutic index.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. js930@cam.ac.uk
authors.forename: John
authors.initials: J
authors.lastname: Skidmore
authors.forename: Zeenat
authors.initials: Z
authors.lastname: Atcha
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Boucherat
authors.forename: Laura
authors.initials: L
authors.lastname: Castelletti
authors.forename: Deborah W
authors.initials: DW
authors.lastname: Chen
authors.forename: Frank T
authors.initials: FT
authors.lastname: Coppo
authors.forename: Leanne
authors.initials: L
authors.lastname: Cutler
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Dunsdon
authors.forename: Bronagh M
authors.initials: BM
authors.lastname: Heath
authors.forename: Rio
authors.initials: R
authors.lastname: Hutchings
authors.forename: David N
authors.initials: DN
authors.lastname: Hurst
authors.forename: Sahar
authors.initials: S
authors.lastname: Javed
authors.forename: Samuel
authors.initials: S
authors.lastname: Martin
authors.forename: Emma S L
authors.initials: ES
authors.lastname: Maskell
authors.forename: David
authors.initials: D
authors.lastname: Norton
authors.forename: Darrel J
authors.initials: DJ
authors.lastname: Pemberton
authors.forename: Sally
authors.initials: S
authors.lastname: Redshaw
authors.forename: Richard
authors.initials: R
authors.lastname: Rutter
authors.forename: Sanjeet S
authors.initials: SS
authors.lastname: Sehmi
authors.forename: Tiziana
authors.initials: T
authors.lastname: Scoccitti
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Temple
authors.forename: Pam
authors.initials: P
authors.lastname: Theobald
authors.forename: Robert W
authors.initials: RW
authors.lastname: Ward
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011817:Rabbits; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor