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 Admin

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• 作者：Mara Prat ; Dolors Fernndez ; M. Antonia Buil ; Mara I. Crespo ; Gaspar Casals ; Manuel Ferrer ; Laia Tort ; Jordi Castro ; Juan M. Monlen ; Amadeu Gavald ; Montserrat Miralpeix ; Israel Ramos ; Teresa Domnech ; D
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 27, 2009
• 年：2009
• 卷：52
• 期：16
• 页码：5076-5092
• 全文大小：1190K
• 年卷期：v.52,no.16(August 27, 2009)
• ISSN：1520-4804

文摘

The 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.