title: The identification of indacaterol as an ultralong-acting inhaled beta2-adrenoceptor agonist.
abstract: Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.
authors.affiliation: Respiratory Diseases Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK.
authors.forename: François
authors.initials: F
authors.lastname: Baur
authors.forename: David
authors.initials: D
authors.lastname: Beattie
authors.forename: David
authors.initials: D
authors.lastname: Beer
authors.forename: David
authors.initials: D
authors.lastname: Bentley
authors.forename: Michelle
authors.initials: M
authors.lastname: Bradley
authors.forename: Ian
authors.initials: I
authors.lastname: Bruce
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Charlton
authors.forename: Bernard
authors.initials: B
authors.lastname: Cuenoud
authors.forename: Roland
authors.initials: R
authors.lastname: Ernst
authors.forename: Robin A
authors.initials: RA
authors.lastname: Fairhurst
authors.forename: Bernard
authors.initials: B
authors.lastname: Faller
authors.forename: David
authors.initials: D
authors.lastname: Farr
authors.forename: Thomas
authors.initials: T
authors.lastname: Keller
authors.forename: John R
authors.initials: JR
authors.lastname: Fozard
authors.forename: Joe
authors.initials: J
authors.lastname: Fullerton
authors.forename: Sheila
authors.initials: S
authors.lastname: Garman
authors.forename: Julia
authors.initials: J
authors.lastname: Hatto
authors.forename: Claire
authors.initials: C
authors.lastname: Hayden
authors.forename: Handan
authors.initials: H
authors.lastname: He
authors.forename: Colin
authors.initials: C
authors.lastname: Howes
authors.forename: Diana
authors.initials: D
authors.lastname: Janus
authors.forename: Zhengjin
authors.initials: Z
authors.lastname: Jiang
authors.forename: Christine
authors.initials: C
authors.lastname: Lewis
authors.forename: Frederique
authors.initials: F
authors.lastname: Loeuillet-Ritzler
authors.forename: Heinz
authors.initials: H
authors.lastname: Moser
authors.forename: John
authors.initials: J
authors.lastname: Reilly
authors.forename: Alan
authors.initials: A
authors.lastname: Steward
authors.forename: David
authors.initials: D
authors.lastname: Sykes
authors.forename: Lauren
authors.initials: L
authors.lastname: Tedaldi
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trifilieff
authors.forename: Morris
authors.initials: M
authors.lastname: Tweed
authors.forename: Simon
authors.initials: S
authors.lastname: Watson
authors.forename: Elke
authors.initials: E
authors.lastname: Wissler
authors.forename: Daniel
authors.initials: D
authors.lastname: Wyss
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists; D000818:Animals; D001993:Bronchodilator Agents / Q000737:chemistry*; D006168:Guinea Pigs; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007189:Indans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D007189:Indans; D015363:Quinolones; C510790:indacaterol