Design and Synthesis of a New Series of 4-Heteroarylamino-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octanes as α7 Nicotinic Receptor Agonists. 1. Development of Pharmacophore and Early Structure–Activity Relationship

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• 作者：James CookF. Christopher Zusi ; Ivar M. McDonald ; Dalton King ; Matthew D. Hill ; Christiana Iwuagwu ; Robert A. Mate ; Haiquan Fang ; Rulin Zhao ; Bei Wang ; Jingfang Cutrone ; Baoqing Ma ; Qi Gao ; Ronald J. Knox ; Michele Matchett ; Lizbeth Gallagher ; Meredith Ferrante ; Debra Post-Munson ; Thaddeus Molski ; Amy Easton ; Regina Miller ; Kelli Jones ; Siva Digavalli ; Francine Healy ; Kimberley Lentz ; Yulia Benitex ; Wendy Clarke ; Joanne Natale ; Judith A. Siuciak ; Nicholas Lodge ; Robert Zaczek ; Rex Denton ; Daniel Morgan ; Linda J. Bristow ; John E. Macor ; Richard E. Olson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 22, 2016
• 年：2016
• 卷：59
• 期：24
• 页码：11171-11181
• 全文大小：606K
• ISSN：1520-4804

文摘

The design and synthesis of a series of quinuclidine-containing spirooxazolidines (“spiroimidates”) and their utility as α7 nicotinic acetylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for α7 over the highly homologous 5-HT_3A receptor. Modification of the N-spiroimidate heterocycle substituent led to (1S,2R,4S)-N-isoquinolin-3-yl)-4′H-4-azaspiro[bicyclo[2.2.2]octane-2,5′oxazol]-2′-amine (BMS-902483), a potent α7 partial agonist, which improved cognition in preclinical rodent models.