2. Academic Validation
  3. 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)

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.
María Prat 1,  Dolors Fernández,  M Antonia Buil,  María I Crespo,  Gaspar Casals,  Manuel Ferrer,  Laia Tort,  Jordi Castro,  Juan M Monleón,  Amadeu Gavaldà,  Montserrat Miralpeix,  Israel Ramos,  Teresa Doménech,  Dolors Vilella,  Francisca Antón,  Josep M Huerta,  Sonia Espinosa,  Manuel López,  Sonia Sentellas,  Marisa González,  Joan Albertí,  Victor Segarra,  Alvaro Cárdenas,  Jorge Beleta,  Hamish Ryder
Affiliations

Affiliation

  • 1 Almirall, R&D Centre, Sant Feliu de Llobregat, Barcelona, Spain. maria.prat@almirall.com
PMID: 19653626 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.

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