Development of 4-Heteroarylamino-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octanes] as α7 Nicotinic Receptor Agonists

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• 作者：Matthew D. HillHaiquan Fang ; H. Dalton King ; Christiana I. Iwuagwu ; Ivar M. McDonald ; James Cook ; F. Christopher ZusiRobert A. Mate ; Ronald J. Knox ; Debra Post-Munson ; Amy Easton ; Regina Miller ; Kimberley Lentz ; Wendy Clarke ; Yulia Benitex ; Nicholas Lodge ; Robert Zaczek ; Rex Denton ; Daniel Morgan ; Linda Bristow ; John E. Macor ; Richard Olson
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：8
• 期：1
• 页码：133-137
• 全文大小：434K
• ISSN：1948-5875

文摘

We describe the synthesis of quinuclidine-containing spiroimidates and their utility as α7 nicotinic acetylcholine receptor (nAChR) partial agonists. A convergent synthetic route allowed for rapid SAR investigation and provided a diverse set of fused 6,5-heteroaryl analogs. Two potent and selective α7 nAChR partial agonists, (1′S,3′R,4′S)-N-(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (20) and (1′S,3′R,4′S)-N-(7-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (21), were identified. Both agonists improved cognition in a preclinical rodent model of learning and memory. Additionally, 5-HT_3A receptor SAR suggested the presence of a steric site that when engaged led to significant loss of affinity at that receptor.