title: Discovery of a novel alpha-7 nicotinic acetylcholine receptor agonist series and characterization of the potent, selective, and orally efficacious agonist 5-(4-acetyl[1,4]diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H-pyrazol-3-yl] amide (SEN15924, WAY-361789).
abstract: Alpha-7 nicotinic acetylcholine receptors (α7 nAChR) are implicated in the modulation of many cognitive functions such as attention, working memory, and episodic memory. For this reason, α7 nAChR agonists represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort, around our previously reported chemical series, permitted the discovery of a novel class of α7 nAChR agonists with improved selectivity, in particular against the α3 receptor subtype and better ADME profile. The exploration of this series led to the identification of 5-(4-acetyl[1,4]diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H-pyrazol-3-yl] amide (25, SEN15924, WAY-361789), a novel, full agonist of the α7 nAChR that was evaluated in vitro and in vivo. Compound 25 proved to be potent and selective, and it demonstrated a fair pharmacokinetic profile accompanied by efficacy in rodent behavioral cognition models (novel object recognition and auditory sensory gating).
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy. riccardozanaletti@hotmail.com
authors.forename: Riccardo
authors.initials: R
authors.lastname: Zanaletti
authors.forename: Laura
authors.initials: L
authors.lastname: Bettinetti
authors.forename: Cristiana
authors.initials: C
authors.lastname: Castaldo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cocconcelli
authors.forename: Thomas
authors.initials: T
authors.lastname: Comery
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gaviraghi
authors.forename: Chiara
authors.initials: C
authors.lastname: Ghiron
authors.forename: Simon N
authors.initials: SN
authors.lastname: Haydar
authors.forename: Flora
authors.initials: F
authors.lastname: Jow
authors.forename: Laura
authors.initials: L
authors.lastname: Maccari
authors.forename: Iolanda
authors.initials: I
authors.lastname: Micco
authors.forename: Arianna
authors.initials: A
authors.lastname: Nencini
authors.forename: Carla
authors.initials: C
authors.lastname: Scali
authors.forename: Elisa
authors.initials: E
authors.lastname: Turlizzi
authors.forename: Michela
authors.initials: M
authors.lastname: Valacchi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020134:Catalytic Domain; D002460:Cell Line; D002463:Cell Membrane Permeability; D003071:Cognition / Q000187:drug effects; D004285:Dogs; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D020318:Rats, Long-Evans; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C574768:5-(4-acetyl(1,4)diazepan-1-yl)pentanoic acid (5-(4-methoxyphenyl)-1H-pyrazol-3-yl) amide; D001381:Azepines; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011720:Pyrazoles; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D002118:Calcium