title: Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile.
abstract: Aclidinium bromide is a novel potent, long-acting inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease. Aclidinium showed subnanomolar affinity for the five human muscarinic receptors (M(1)-M(5)). [(3)H]Aclidinium dissociated slightly faster from M(2) and M(3) receptors than [(3)H]tiotropium but much more slowly than [(3)H]ipratropium. Its association rate for the M(3) receptor was similar to [(3)H]ipratropium and 2.6 times faster than [(3)H]tiotropium. Residence half-life of [(3)H]aclidinium at the M(2) receptor was shorter than at the M(3) receptor, demonstrating kinetic selectivity for the M(3) receptor. In isolated guinea pig trachea, aclidinium showed comparable potency to ipratropium and tiotropium, faster onset of action than tiotropium, and duration of action similar to tiotropium and significantly longer than ipratropium. Nebulized aclidinium inhibited bronchoconstriction induced by acetylcholine in guinea pigs in a concentration-dependent manner with an onset of action faster than tiotropium. Duration of action of aclidinium (t(1/2) = 29 h) was much longer than ipratropium (8 h) but shorter than tiotropium (64 h). In dogs, aclidinium induced a smaller and more transient increase in heart rate than tiotropium at comparable supratherapeutic doses. Therefore, under these conditions, aclidinium showed a greater therapeutic index than tiotropium (4.2 versus 1.6). These results indicate that aclidinium is a potent muscarinic antagonist with a fast onset of action, a long duration of effect, and a favorable cardiovascular safety profile.
authors.affiliation: Almirall, Biology Department, R&D Center, Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Amadeu
authors.initials: A
authors.lastname: Gavaldà
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
authors.forename: Israel
authors.initials: I
authors.lastname: Ramos
authors.forename: Raquel
authors.initials: R
authors.lastname: Otal
authors.forename: Cristina
authors.initials: C
authors.lastname: Carreño
authors.forename: Marisa
authors.initials: M
authors.lastname: Viñals
authors.forename: Teresa
authors.initials: T
authors.lastname: Doménech
authors.forename: Carla
authors.initials: C
authors.lastname: Carcasona
authors.forename: Blanca
authors.initials: B
authors.lastname: Reyes
authors.forename: Dolors
authors.initials: D
authors.lastname: Vilella
authors.forename: Jordi
authors.initials: J
authors.lastname: Gras
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
authors.forename: Esteban
authors.initials: E
authors.lastname: Morcillo
authors.forename: Jesús
authors.initials: J
authors.lastname: Llenas
authors.forename: Hamish
authors.initials: H
authors.lastname: Ryder
authors.forename: Jorge
authors.initials: J
authors.lastname: Beleta
mesh_terms: D000280:Administration, Inhalation; D000758:Anesthesia; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D009241:Ipratropium / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects; D012602:Scopolamine Derivatives / Q000494:pharmacology; D013268:Stimulation, Chemical; D000069447:Tiotropium Bromide; D014132:Trachea / Q000187:drug effects; D014326:Tropanes / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D014326:Tropanes; D002217:Carbachol; D009241:Ipratropium; C542859:aclidinium bromide; D000069447:Tiotropium Bromide