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).
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Prat M, Fernandez D, Buil MA, Crespo MI, Casals G, Ferrer M, Tort L, Castro J, Monleon JM, Gavalda A, Miralpeix M, Ramos I, Domenech T, Vilella D, Anton F, Huerta JM, Espinosa S, Lopez M, Sentellas S, Gonzalez M, Alberti J, Segarra V, Cardenas A, Beleta J, Ryder H
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.
- PubMed ID
- 19653626 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Aclidinium Muscarinic acetylcholine receptor M1 Ki (nM) 0.08 N/A N/A Details Aclidinium Muscarinic acetylcholine receptor M1 IC 50 (nM) 0.14 N/A N/A Details Aclidinium Muscarinic acetylcholine receptor M2 Ki (nM) 0.08 N/A N/A Details Aclidinium Muscarinic acetylcholine receptor M2 IC 50 (nM) 0.17 N/A N/A Details Aclidinium Muscarinic acetylcholine receptor M3 Ki (nM) 0.07 N/A N/A Details Aclidinium Muscarinic acetylcholine receptor M3 IC 50 (nM) 0.17 N/A N/A Details