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 PMID: 27958732

Target-related Cytokines

2026-09-23

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

J Med Chem. 2016 Dec 22;59(24):11171-11181. doi: 10.1021/acs.jmedchem.6b01506.

James Cook ¹ , F Christopher Zusi ¹ , Ivar M McDonald ¹ , Dalton King ¹ , Matthew D Hill ¹ , Christiana Iwuagwu ¹ , Robert A Mate ¹ , Haiquan Fang ¹ , Rulin Zhao ¹ , Bei Wang ¹ , Jingfang Cutrone ¹ , Baoqing Ma ¹ , Qi Gao ¹ , Ronald J Knox ¹ , Michele Matchett ¹ , Lizbeth Gallagher ¹ , Meredith Ferrante ¹ , Debra Post-Munson ¹ , Thaddeus Molski ¹ , Amy Easton ¹ , Regina Miller ¹ , Kelli Jones ¹ , Siva Digavalli ¹ , Francine Healy ¹ , Kimberley Lentz ¹ , Yulia Benitex ¹ , Wendy Clarke ¹ , Joanne Natale ¹ , Judith A Siuciak ¹ , Nicholas Lodge ¹ , Robert Zaczek ¹ , Rex Denton ¹ , Daniel Morgan ¹ , Linda J Bristow ¹ , John E Macor ¹ , Richard E Olson ¹

Affiliations

Abstract

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.