Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists

Bioorg Med Chem Lett. 2015 Apr 15;25(8):1736-1741. doi: 10.1016/j.bmcl.2015.02.065. Epub 2015 Mar 5.

Abstract

Novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides have been identified as potent M3 muscarinic antagonists with a long duration of action in an in vivo model of bronchoconstriction. The synthesis, structure-activity relationships and biological evaluation of this series of compounds are reported.

Keywords: (3R)-Quinuclidinyl amides; COPD; Long acting bronchodilators; Low systemic exposure; M(3) muscarinic antagonists.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Animals
  • Binding Sites
  • Bronchoconstrictor Agents / chemical synthesis
  • Bronchoconstrictor Agents / chemistry
  • Bronchoconstrictor Agents / pharmacokinetics
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Hydrogen Bonding
  • Molecular Docking Simulation
  • Muscarinic Antagonists / chemical synthesis
  • Muscarinic Antagonists / chemistry*
  • Muscarinic Antagonists / pharmacokinetics
  • Protein Binding
  • Protein Structure, Tertiary
  • Quaternary Ammonium Compounds / chemistry*
  • Quinuclidines / chemistry*
  • Rats
  • Receptor, Muscarinic M3 / antagonists & inhibitors*
  • Receptor, Muscarinic M3 / metabolism
  • Structure-Activity Relationship

Substances

  • Amides
  • Bronchoconstrictor Agents
  • Muscarinic Antagonists
  • Quaternary Ammonium Compounds
  • Quinuclidines
  • Receptor, Muscarinic M3