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
2016-11-18T00:00:00Z (GMT) by
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<sub>3A</sub> receptor. Modification of the <i>N</i>-spiroimidate heterocycle substituent led to (1<i>S</i>,2<i>R</i>,4<i>S</i>)-<i>N</i>-isoquinolin-3-yl)-4′<i>H</i>-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.