title: 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).
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.
authors: Almirall, R&D Centre, Sant Feliu de Llobregat, Barcelona, Spain. maria.prat@almirall.com
authors: María
authors: M
authors: Prat
authors: Dolors
authors: D
authors: Fernández
authors: M Antonia
authors: MA
authors: Buil
authors: María I
authors: MI
authors: Crespo
authors: Gaspar
authors: G
authors: Casals
authors: Manuel
authors: M
authors: Ferrer
authors: Laia
authors: L
authors: Tort
authors: Jordi
authors: J
authors: Castro
authors: Juan M
authors: JM
authors: Monleón
authors: Amadeu
authors: A
authors: Gavaldà
authors: Montserrat
authors: M
authors: Miralpeix
authors: Israel
authors: I
authors: Ramos
authors: Teresa
authors: T
authors: Doménech
authors: Dolors
authors: D
authors: Vilella
authors: Francisca
authors: F
authors: Antón
authors: Josep M
authors: JM
authors: Huerta
authors: Sonia
authors: S
authors: Espinosa
authors: Manuel
authors: M
authors: López
authors: Sonia
authors: S
authors: Sentellas
authors: Marisa
authors: M
authors: González
authors: Joan
authors: J
authors: Albertí
authors: Victor
authors: V
authors: Segarra
authors: Alvaro
authors: A
authors: Cárdenas
authors: Jorge
authors: J
authors: Beleta
authors: Hamish
authors: H
authors: Ryder
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001986:Bronchial Spasm / Q000188:drug therapy / Q000503:physiopathology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004355:Drug Stability; D004952:Esters; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043587:Receptor, Muscarinic M3 / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004952:Esters; D018727:Muscarinic Antagonists; D000644:Quaternary Ammonium Compounds; D011812:Quinuclidines; D043587:Receptor, Muscarinic M3; D014326:Tropanes; C542859:aclidinium bromide