1. Academic Validation
  2. 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

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

Affiliation

  • 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.

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