Аклидиния бромид

Описание

In July 2012, aclidinium bromide was approved in the US and the EU for long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disorder (COPD). Aclidinium bromide is in the latter category, acting as a selective antagonist for the muscarinic M3 receptor. M3 receptors are localized in airway smooth muscle, and are the primary subtype responsible for bronchial and tracheal smooth muscle contraction. Muscarinic antagonists are well-established bronchodilators that are effective for treating COPD, but these agents have unwanted side effects if systemically absorbed. Systemic exposure can be limited by inhaled administration, which is the route of delivery for aclidinium bromide. In addition, aclidinium bromide was designed to undergo rapid hydrolysis in human plasma, providing inactive acid and alcohol products, and reducing the potential for systemic side effects. Aclidinium bromide was identified amongst a series of quaternary ammonium (3R)-quinuclidinol esters as having the best combination of high potency (M3 Ki=0.14 nM), long duration of action (29 h for 50% reduction of therapeutic effect in a guinea pig bronchoconstriction model), low oral absorption, and rapid plasma degradation. The synthesis of aclidinium bromide was achieved by reaction of dimethyl oxalate with 2-thienylmagnesium bromide followed by treatment of the resulting methyl ester with (3R)-quinuclidinol in the presence of sodium hydride. Quaternization of the amine was achieved by treatment with 3-phenoxypropyl bromide to give aclidinium bromide.

Использование

Aclidinium Bromide inhibits human muscarinic AChR M1, M2, M3, M4 and M5 with Ki of 0.1 nM, 0.14 nM, 0.14 nM, 0.21 nM and 0.16 nM, respectively

Определение

ChEBI: A quaternary ammonium salt that is the bromide salt of aclidinium. A muscarinic acetylcholine M3 receptor antagonist, for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).

Клиническое использование

Aclidinium bromide was approved by the U. S. Food and Drug Administration (FDA) in July 2012 for the treatment of chronic obstructive pulmonary disease (COPD). Marketed by Forest Pharmaceuticals, aclidinium bromide selectively binds to five human muscarinic receptors (M1-M5), and posesses a subnanomolar binding affinity for these particular targets. Administered by inhalation, this medicine has demonstrated favorable onset and duration of action, and its safety profile is an improvement over competitor therapies.