title: An investigation into the structure-activity relationships associated with the systematic modification of the β(2)-adrenoceptor agonist indacaterol.
abstract: The synthesis of a series of indacaterol analogues in which each of the three structural regions of indacaterol are modified in a systematic manner is described. Evaluation of the affinity of these analogues for the β(2)-adrenoceptor identified the 3,4-dihydroquinolinone and 5-n-butylindanyl analogues to demonstrate the most similar profiles to indacaterol. An α-methyl aminoindane analogue was discovered to be 25-fold more potent than indacaterol, and functional studies revealed an atypical β(2)-adrenoceptor activation profile for this compound consistent with that of a slowly dissociating 'super agonist'.
authors.affiliation: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Beattie
authors.forename: David
authors.initials: D
authors.lastname: Beer
authors.forename: Michelle E
authors.initials: ME
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 M
authors.initials: BM
authors.lastname: Cuenoud
authors.forename: Robin A
authors.initials: RA
authors.lastname: Fairhurst
authors.forename: David
authors.initials: D
authors.lastname: Farr
authors.forename: John R
authors.initials: JR
authors.lastname: Fozard
authors.forename: Diana
authors.initials: D
authors.lastname: Janus
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Rosethorne
authors.forename: David A
authors.initials: DA
authors.lastname: Sandham
authors.forename: David A
authors.initials: DA
authors.lastname: Sykes
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trifilieff
authors.forename: Katharine L
authors.initials: KL
authors.lastname: Turner
authors.forename: Elke
authors.initials: E
authors.lastname: Wissler
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D007189:Indans; D015363:Quinolones; D018343:Receptors, Adrenergic, beta-2; C510790:indacaterol