jm6b01506_si_002.csv (3.1 kB)
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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posted on 2016-11-18, 00:00 authored by James Cook, F. 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. OlsonThe
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-HT3A 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.
