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. Epub 2016 Dec 13.

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.

MeSH terms

  • Animals
  • Cyclooctanes / chemical synthesis
  • Cyclooctanes / chemistry
  • Cyclooctanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Maze Learning / drug effects
  • Mice
  • Molecular Structure
  • Nicotinic Agonists / chemical synthesis
  • Nicotinic Agonists / chemistry
  • Nicotinic Agonists / pharmacology*
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship
  • alpha7 Nicotinic Acetylcholine Receptor / antagonists & inhibitors*

Substances

  • Cyclooctanes
  • Nicotinic Agonists
  • Spiro Compounds
  • alpha7 Nicotinic Acetylcholine Receptor