The identification of indacaterol as an ultralong-acting inhaled beta2-adrenoceptor agonist.
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.
Baur
François
F
Respiratory Diseases Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK.
Beattie
David
D
Beer
David
D
Bentley
David
D
Bradley
Michelle
M
Bruce
Ian
I
Charlton
Steven J
SJ
Cuenoud
Bernard
B
Ernst
Roland
R
Fairhurst
Robin A
RA
Faller
Bernard
B
Farr
David
D
Keller
Thomas
T
Fozard
John R
JR
Fullerton
Joe
J
Garman
Sheila
S
Hatto
Julia
J
Hayden
Claire
C
He
Handan
H
Howes
Colin
C
Janus
Diana
D
Jiang
Zhengjin
Z
Lewis
Christine
C
Loeuillet-Ritzler
Frederique
F
Moser
Heinz
H
Reilly
John
J
Steward
Alan
A
Sykes
David
D
Tedaldi
Lauren
L
Trifilieff
Alexandre
A
Tweed
Morris
M
Watson
Simon
S
Wissler
Elke
E
Wyss
Daniel
D
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
D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D007189:Indans; D015363:Quinolones; C510790:indacaterol