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)

被引:25
|
作者
Zanaletti, Riccardo [1 ]
Bettinetti, Laura [1 ]
Castaldo, Cristiana [1 ]
Cocconcelli, Giuseppe [1 ]
Comery, Thomas [2 ]
Dunlop, John [2 ]
Gaviraghi, Giovanni [1 ]
Ghiron, Chiara [1 ]
Haydar, Simon N. [2 ]
Jow, Flora [2 ]
Maccari, Laura [1 ]
Micco, Iolanda [1 ]
Nencini, Arianna [1 ]
Scali, Carla [1 ]
Turlizzi, Elisa [1 ]
Valacchit, Michela [1 ]
机构
[1] Siena Biotech SpA, I-53100 Siena, Italy
[2] Pfizer Inc, Neurosci Res Unit, Groton, CT 06340 USA
关键词
IN-VITRO; TARGETS; SCHIZOPHRENIA; INHIBITION; BINDING; ASSAYS;
D O I
10.1021/jm300247y
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Alpha-7 nicotinic acetylcholine receptors (alpha 7 nAChR) are implicated in the modulation of many cognitive functions such as attention, working memory, and episodic memory. For this reason, alpha 7 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 alpha 7 nAChR agonists with improved selectivity, in particular against the alpha 3 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 alpha 7 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).
引用
收藏
页码:4806 / 4823
页数:18
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