Aclidinium bromide

Description

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.

Originator

Almirall (Spain)

The Uses of Aclidinium bromide

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

The Uses of Aclidinium bromide

Aclidinium Bromide is a novel long-acting antimuscarinic bronchodilator in phase II clinical trials for the treatment of chronic obstructive pulmonary disease.

Definition

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).

brand name

Tudorza Pressair? (US) Eklira?/Bretaris? Genuair? (EU)

Clinical Use

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.

Synthesis

No manufacturing route has been disclosed to date, the most scalable published synthesis is described in the scheme. Dimethyl oxalate (1) was initially treated with two equivalents of Grignard 2 to give bis-thiophenoate 3 in 36% yield. Subsequent transesterification with (R)-quinuclidinol (4) gave rise to the quinuclidine-containing ester 5 in 50% yield. Aclidinium bromide (I) could be accessed by two different methods involving bromoalkyl phenyl ether 6?aan excess of bromide in the presence of an acetonitrile/chloroform mixture gave the drug in 89% isolated yield, or with fewer equivalents of electrophile (1.25 eq) during exposure to refluxing acetophenone has reportedly delivered (I) quantitatively on multi-gram scale.17 From commercial 2, the multi-gram synthesis of Aclidinium bromide (I) was completed in 17.8% over three steps.

References

[1] gavaldà a1, ramos i2, carcasona c3, calama e4, otal r5, montero jl6, sentellas s7, aparici m8, vilella d9, alberti j10, beleta j11, miralpeix m12. the in vitro and in vivo profile of aclidinium bromide in comparison with glycopyrronium bromide. pulm pharmacol ther. 2014 aug;28(2):114-21.