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)

Riccardo Zanaletti; Laura Bettinetti; Cristiana Castaldo; Giuseppe Cocconcelli; Thomas Comery; John Dunlop; Giovanni Gaviraghi; Chiara Ghiron; Simon N Haydar; Flora Jow; Laura Maccari; Iolanda Micco; Arianna Nencini; Carla Scali; Elisa Turlizzi; Michela Valacchi

doi:10.1021/jm300247y

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)

J Med Chem. 2012 May 24;55(10):4806-23. doi: 10.1021/jm300247y. Epub 2012 May 3.

Authors

Riccardo Zanaletti¹, Laura Bettinetti, Cristiana Castaldo, Giuseppe Cocconcelli, Thomas Comery, John Dunlop, Giovanni Gaviraghi, Chiara Ghiron, Simon N Haydar, Flora Jow, Laura Maccari, Iolanda Micco, Arianna Nencini, Carla Scali, Elisa Turlizzi, Michela Valacchi

Affiliation

¹ Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy. riccardozanaletti@hotmail.com

PMID: 22468936
DOI: 10.1021/jm300247y

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).

MeSH terms

Administration, Oral
Animals
Azepines / chemical synthesis*
Azepines / pharmacokinetics
Azepines / pharmacology
Brain / metabolism
Calcium / metabolism
Catalytic Domain
Cell Line
Cell Membrane Permeability
Cognition / drug effects
Dogs
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
Humans
Male
Membrane Potentials / drug effects
Models, Molecular
Nicotinic Agonists / chemical synthesis*
Nicotinic Agonists / pharmacokinetics
Nicotinic Agonists / pharmacology
Nicotinic Antagonists / chemical synthesis
Nicotinic Antagonists / pharmacokinetics
Nicotinic Antagonists / pharmacology
Patch-Clamp Techniques
Pyrazoles / chemical synthesis*
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology
Radioligand Assay
Rats
Rats, Long-Evans
Receptors, Nicotinic / metabolism*
Reflex, Startle / drug effects
Structure-Activity Relationship
alpha7 Nicotinic Acetylcholine Receptor

Substances

5-(4-acetyl(1,4)diazepan-1-yl)pentanoic acid (5-(4-methoxyphenyl)-1H-pyrazol-3-yl) amide
Azepines
Chrna7 protein, human
Chrna7 protein, rat
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Nicotinic Agonists
Nicotinic Antagonists
Pyrazoles
Receptors, Nicotinic
alpha7 Nicotinic Acetylcholine Receptor
Calcium