title: Novel alpha-7 nicotinic acetylcholine receptor agonists containing a urea moiety: identification and characterization of the potent, selective, and orally efficacious agonist 1-[6-(4-fluorophenyl)pyridin-3-yl]-3-(4-piperidin-1-ylbutyl) urea (SEN34625/WYE-103914).
abstract: Alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the alpha7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the alpha7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.
authors.affiliation: Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy. cghiron@sienabiotech.it
authors.forename: Chiara
authors.initials: C
authors.lastname: Ghiron
authors.forename: Simon N
authors.initials: SN
authors.lastname: Haydar
authors.forename: Suzan
authors.initials: S
authors.lastname: Aschmies
authors.forename: Hendrick
authors.initials: H
authors.lastname: Bothmann
authors.forename: Cristiana
authors.initials: C
authors.lastname: Castaldo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cocconcelli
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Comery
authors.forename: Li
authors.initials: L
authors.lastname: Di
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.forename: Tim
authors.initials: T
authors.lastname: Lock
authors.forename: Angela
authors.initials: A
authors.lastname: Kramer
authors.forename: Dianne
authors.initials: D
authors.lastname: Kowal
authors.forename: Flora
authors.initials: F
authors.lastname: Jow
authors.forename: Steve
authors.initials: S
authors.lastname: Grauer
authors.forename: Boyd
authors.initials: B
authors.lastname: Harrison
authors.forename: Salvatore
authors.initials: S
authors.lastname: La Rosa
authors.forename: Laura
authors.initials: L
authors.lastname: Maccari
authors.forename: Karen L
authors.initials: KL
authors.lastname: Marquis
authors.forename: Iolanda
authors.initials: I
authors.lastname: Micco
authors.forename: Arianna
authors.initials: A
authors.lastname: Nencini
authors.forename: Joanna
authors.initials: J
authors.lastname: Quinn
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
authors.forename: Renza
authors.initials: R
authors.lastname: Roncarati
authors.forename: Carla
authors.initials: C
authors.lastname: Scali
authors.forename: Georg C
authors.initials: GC
authors.lastname: Terstappen
authors.forename: Elisa
authors.initials: E
authors.lastname: Turlizzi
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
authors.forename: Ugo
authors.initials: U
authors.lastname: Zanelli
mesh_terms: D000284:Administration, Oral; D000818:Animals; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011487:Protein Conformation; D011725:Pyridines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C550466:1-(6-(4-fluorophenyl)pyridin-3-yl)-3-(4-piperidin-1-ylbutyl)urea; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D014508:Urea