Development of 4-Heteroarylamino-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octanes] as α7 Nicotinic Receptor Agonists

  • ACS Med Chem Lett. 2016 Dec 1;8(1):133-137. doi: 10.1021/acsmedchemlett.6b00471.
Matthew D Hill  1 ,  Haiquan Fang  1 ,  H Dalton King  1 ,  Christiana I Iwuagwu  1 ,  Ivar M McDonald  1 ,  James Cook  1 ,  F Christopher Zusi  1 ,  Robert A Mate  1 ,  Ronald J Knox  1 ,  Debra Post-Munson  1 ,  Amy Easton  1 ,  Regina Miller  1 ,  Kimberley Lentz  1 ,  Wendy Clarke  1 ,  Yulia Benitex  1 ,  Nicholas Lodge  1 ,  Robert Zaczek  1 ,  Rex Denton  1 ,  Daniel Morgan  1 ,  Linda Bristow  1 ,  John E Macor  1 ,  Richard Olson  1
Affiliations
  • 1. Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
PMID: 28105289 DOI: 10.1021/acsmedchemlett.6b00471
Abstract

We describe the synthesis of quinuclidine-containing spiroimidates and their utility as α7 nicotinic acetylcholine receptor (nAChR) partial agonists. A convergent synthetic route allowed for rapid SAR investigation and provided a diverse set of fused 6,5-heteroaryl analogs. Two potent and selective α7 nAChR partial agonists, (1'S,3'R,4'S)-N-(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine (20) and (1'S,3'R,4'S)-N-(7-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine (21), were identified. Both agonists improved cognition in a preclinical rodent model of learning and memory. Additionally, 5-HT3A receptor SAR suggested the presence of a steric site that when engaged led to significant loss of affinity at that receptor.

Keywords
novel object recognition; quinuclidine; schizophrenia; α7 nAChR.