N-[5-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl]-4-piperidin-1-ylbutyramide (SEN78702, WYE-308775): a medicinal chemistry effort toward an α7 nicotinic acetylcholine receptor agonist preclinical candidate.
α7 Nicotinic acetylcholine receptors (α7 nAChR) represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort around previously reported compound 1 (SEN15924, WAY-361789) led to the identification of 12 (SEN78702, WYE-308775) a potent and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models.
Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy. riccardozanaletti@hotmail.com
Riccardo
R
Zanaletti
Laura
L
Bettinetti
Cristiana
C
Castaldo
Ilaria
I
Ceccarelli
Giuseppe
G
Cocconcelli
Thomas A
TA
Comery
John
J
Dunlop
Eva
E
Genesio
Chiara
C
Ghiron
Simon N
SN
Haydar
Flora
F
Jow
Laura
L
Maccari
Iolanda
I
Micco
Arianna
A
Nencini
Carmela
C
Pratelli
Carla
C
Scali
Elisa
E
Turlizzi
Michela
M
Valacchi
D000818:Animals; D001921:Brain / Q000187:drug effects*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D003071:Cognition / Q000187:drug effects*; D006224:Cricetinae; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C577963:N-(5-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl)-4-piperidin-1-ylbutyramide; D018722:Nicotinic Agonists; D010880:Piperidines; D011720:Pyrazoles; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D002118:Calcium