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).
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.
Prat
María
M
Almirall, R&D Centre, Sant Feliu de Llobregat, Barcelona, Spain. maria.prat@almirall.com
Fernández
Dolors
D
Buil
M Antonia
MA
Crespo
María I
MI
Casals
Gaspar
G
Ferrer
Manuel
M
Tort
Laia
L
Castro
Jordi
J
Monleón
Juan M
JM
Gavaldà
Amadeu
A
Miralpeix
Montserrat
M
Ramos
Israel
I
Doménech
Teresa
T
Vilella
Dolors
D
Antón
Francisca
F
Huerta
Josep M
JM
Espinosa
Sonia
S
López
Manuel
M
Sentellas
Sonia
S
González
Marisa
M
Albertí
Joan
J
Segarra
Victor
V
Cárdenas
Alvaro
A
Beleta
Jorge
J
Ryder
Hamish
H
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
D004952:Esters; D018727:Muscarinic Antagonists; D000644:Quaternary Ammonium Compounds; D011812:Quinuclidines; D043587:Receptor, Muscarinic M3; D014326:Tropanes; C542859:aclidinium bromide