title: SAR and biological evaluation of SEN12333/WAY-317538: Novel alpha 7 nicotinic acetylcholine receptor agonist.
abstract: Alpha 7 nicotinic acetylcholine receptor (alpha(7) nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment associated with a variety of disorders including Alzheimer's disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions associated with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer's disease. Herein we report a novel, potent small molecule agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compound is a selective agonist of the alpha(7) nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioural cognition models. The SAR and biological evaluation of this series of compounds are discussed.
authors.affiliation: Chemical Sciences and Neuroscience Discovery Research, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA. haydars@wyeth.com
authors.forename: Simon N
authors.initials: SN
authors.lastname: Haydar
authors.forename: Chiara
authors.initials: C
authors.lastname: Ghiron
authors.forename: Laura
authors.initials: L
authors.lastname: Bettinetti
authors.forename: Hendrick
authors.initials: H
authors.lastname: Bothmann
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Comery
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.forename: Salvatore
authors.initials: S
authors.lastname: La Rosa
authors.forename: Iolanda
authors.initials: I
authors.lastname: Micco
authors.forename: Martina
authors.initials: M
authors.lastname: Pollastrini
authors.forename: Joanna
authors.initials: J
authors.lastname: Quinn
authors.forename: Renza
authors.initials: R
authors.lastname: Roncarati
authors.forename: Carla
authors.initials: C
authors.lastname: Scali
authors.forename: Michela
authors.initials: M
authors.lastname: Valacchi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Varrone
authors.forename: Riccardo
authors.initials: R
authors.lastname: Zanaletti
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003071:Cognition / Q000187:drug effects; D004594:Electrophysiology; D006801:Humans; D009025:Morpholines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C540749:5-morpholin-4-ylpentanoic acid (4-pyridin-3-ylphenyl)amide; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D009025:Morpholines; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D002118:Calcium