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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 24, 2012
• 年：2012
• 卷：55
• 期：10
• 页码：4806-4823
• 全文大小：672K
• 年卷期：v.55,no.10(May 24, 2012)
• ISSN：1520-4804

文摘

Alpha-7 nicotinic acetylcholine receptors (伪7 nAChR) are implicated in the modulation of many cognitive functions such as attention, working memory, and episodic memory. For this reason, 伪7 nAChR agonists represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer鈥檚 disease (AD) and schizophrenia. A medicinal chemistry effort, around our previously reported chemical series, permitted the discovery of a novel class of 伪7 nAChR agonists with improved selectivity, in particular against the 伪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 伪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).