Design and synthesis of a hybrid series of potent and selective agonists of α7 nicotinic acetylcholine receptor.
α7 nicotinic acetylcholine receptor agonists are promising therapeutic candidates for the treatment of cognitive impairment. As a follow up of our internal medicinal chemistry program we investigated a novel series of α7 nAChR agonists. Starting from molecular docking studies on two series of molecules recently developed in our laboratories, an alternative scaffold was designed attempting to combine the optimal features of these previously identified urea and pyrazole compounds. Based on our previous SAR knowledge and on predicted drug-like properties, a small library was synthesized in parallel manner, affording compounds with excellent α7 nAChR activity, selectivity and preliminary ADME profile.
Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy. Electronic address: anencini@sienabiotech.it.
Arianna
A
Nencini
Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
Cristiana
C
Castaldo
Neuroscience Research Unit, Pfizer, Eastern Point Road, Groton, CT 06340, United States.
Thomas A
TA
Comery
Neuroscience Research Unit, Pfizer, Eastern Point Road, Groton, CT 06340, United States.
John
J
Dunlop
Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
Eva
E
Genesio
Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
Chiara
C
Ghiron
Neuroscience Research Unit, Pfizer, Eastern Point Road, Groton, CT 06340, United States.
Simon
S
Haydar
Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
Laura
L
Maccari
Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
Iolanda
I
Micco
Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
Elisa
E
Turlizzi
Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
Riccardo
R
Zanaletti
Neuroscience Research Unit, Pfizer, Eastern Point Road, Groton, CT 06340, United States.
Jean
J
Zhang
D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
D011720:Pyrazoles; D064569:alpha7 Nicotinic Acetylcholine Receptor; C031280:pyrazole; D014508:Urea
Alzheimer's disease; Cognition; Neuronal nicotinic acetylcholine receptors; Nicotinic ligands; Schizophrenia