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)

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.

Characterization of Aclidinium Bromide, a Novel Inhaled Muscarinic Antagonist, with Long Duration of Action and a Favorable Pharmacological Profile

“…Aclidinium bromide, 3R-(2-hydroxy-2,2-dithiophen-2-yl-acetoxy)-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2] octane bromide (Fig. 1), previously known as LAS34273, is a novel inhaled muscarinic antagonist (Prat et al, 2009) currently being studied in phase III clinical trials for the maintenance treatment of COPD (NCT00363896, NCT00358436, www.ClinTrials.gov, 2008). In contrast to other currently available antimuscarinics including tiotropium, aclidinium has been shown to undergo rapid hydrolysis in human plasma, resulting in very low and transient systemic exposure, suggesting a reduced potential for classrelated systemic side effects in the clinical setting .…”

Identification of the Human Enzymes Responsible for the Enzymatic Hydrolysis of Aclidinium Bromide

“…It is intended for the maintenance treatment of chronic obstructive pulmonary disease. Aclidinium showed nonenzymatic hydrolysis of its ester bond at neutral and basic pH and was rapidly hydrolyzed in plasma of different animal species and humans to yield an alcohol (LAS34823, [3(R)-hydroxy-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane, bromide]) and carboxylic acid metabolite (LAS34850, [dithienyl-glycolic acid, sodium salt]) (Prat et al, 2009). The marked difference in the rate of aclidinium hydrolysis observed in human plasma (t 1/2 , 2.4 min) and in phosphate buffer at pH 7.4 (t 1/2 , 1.2 h) suggested that enzymatic hydrolysis plays a major role in the overall hydrolysis of aclidinium (Sentellas et al, 2010).…”

The safety of anticholinergic bronchodilators for the treatment of chronic obstructive pulmonary disease

“…Aclidinium is a new inhaled, long-acting muscarinic antagonist with a comparatively low potential for systemic side effects due to its rapid hydrolysis to two major inactive metabolites once it is absorbed into the circulation [74][75][76]. It was initially studied in a dose of 200 mcg once daily delivered from a multi-dose dry powder inhaler (Genuair or Pressair) but its bronchodilator efficacy at 24 hrs was relatively modest [77].…”