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
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.