SAR and biological evaluation of SEN12333/WAY-317538: Novel alpha 7 nicotinic acetylcholine receptor agonist.
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.
Haydar
Simon N
SN
Chemical Sciences and Neuroscience Discovery Research, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA. haydars@wyeth.com
Ghiron
Chiara
C
Bettinetti
Laura
L
Bothmann
Hendrick
H
Comery
Thomas A
TA
Dunlop
John
J
La Rosa
Salvatore
S
Micco
Iolanda
I
Pollastrini
Martina
M
Quinn
Joanna
J
Roncarati
Renza
R
Scali
Carla
C
Valacchi
Michela
M
Varrone
Maurizio
M
Zanaletti
Riccardo
R
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
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