Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide)

J Med Chem. 2009 Aug 27;52(16):5076-92. doi: 10.1021/jm900132z.

Abstract

The objective of this work was to discover a novel, long-acting muscarinic M(3) antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Animals
  • Bronchial Spasm / drug therapy
  • Bronchial Spasm / physiopathology
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Drug Stability
  • Esters
  • Guinea Pigs
  • Humans
  • Male
  • Mice
  • Muscarinic Antagonists / chemical synthesis*
  • Muscarinic Antagonists / chemistry
  • Muscarinic Antagonists / pharmacology
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Quaternary Ammonium Compounds / chemical synthesis*
  • Quaternary Ammonium Compounds / chemistry
  • Quaternary Ammonium Compounds / pharmacology
  • Quinuclidines / chemical synthesis*
  • Quinuclidines / chemistry
  • Quinuclidines / pharmacology
  • Radioligand Assay
  • Receptor, Muscarinic M3 / physiology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tropanes / chemical synthesis*
  • Tropanes / chemistry
  • Tropanes / pharmacology

Substances

  • Esters
  • Muscarinic Antagonists
  • Quaternary Ammonium Compounds
  • Quinuclidines
  • Receptor, Muscarinic M3
  • Tropanes
  • aclidinium bromide