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).
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.
Ghiron
Chiara
C
Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy. cghiron@sienabiotech.it
Haydar
Simon N
SN
Aschmies
Suzan
S
Bothmann
Hendrick
H
Castaldo
Cristiana
C
Cocconcelli
Giuseppe
G
Comery
Thomas A
TA
Di
Li
L
Dunlop
John
J
Lock
Tim
T
Kramer
Angela
A
Kowal
Dianne
D
Jow
Flora
F
Grauer
Steve
S
Harrison
Boyd
B
La Rosa
Salvatore
S
Maccari
Laura
L
Marquis
Karen L
KL
Micco
Iolanda
I
Nencini
Arianna
A
Quinn
Joanna
J
Robichaud
Albert J
AJ
Roncarati
Renza
R
Scali
Carla
C
Terstappen
Georg C
GC
Turlizzi
Elisa
E
Valacchi
Michela
M
Varrone
Maurizio
M
Zanaletti
Riccardo
R
Zanelli
Ugo
U
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
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