Discovery of Novel Quaternary Ammonium Derivatives of (3 R )-Quinuclidinol Esters as Potent and Long-Acting Muscarinic Antagonists with Potential for Minimal Systemic Exposure after Inhaled Administration: Identification of (3 R )-3-{[Hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane Bromide (Aclidinium Bromide)
2009; American Chemical Society; Volume: 52; Issue: 16 Linguagem: Inglês
10.1021/jm900132z
ISSN1520-4804
AutoresMaría Prat, Dolors Fernández, María Antonia Buil, M. Crespo, Gaspar Casals, Manuel Ferrer, Laia Tort, Jordi Castro, Juan Manuel Monleón, Amadeu Gavaldà, Montserrat Miralpeix, Israel Ramos, Teresa Domènech, Dolors Vilella, Francisca Antón, José María Huerta, Sònia Espinosa, Manuel López, Sònia Sentellas, Marisa González, Joan Albertí, Vı́ctor Segarra, Á. de Pablo Cárdenas, Jörge Beleta, Hamish Ryder,
Tópico(s)Pneumonia and Respiratory Infections
ResumoThe objective of this work was to discover a novel, long-acting muscarinic M3 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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