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
  • 1. Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
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-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.