An investigation into the structure-activity relationships associated with the systematic modification of the beta(2)-adrenoceptor agonist indacaterol

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 19; pp. 6280 - 6285
• Main Authors: Beattie, David, Beer, David, Bradley, Michelle E., Bruce, Ian, Charlton, Steven J., Cuenoud, Bernard M., Fairhurst, Robin A., Farr, David, Fozard, John R., Janus, Diana, Rosethorne, Elizabeth M., Sandham, David A., Sykes, David A., Trifilieff, Alexandre, Turner, Katharine L., Wissler, Elke
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 01.10.2012
• Subjects: Adrenergic beta-2 Receptor Agonists - chemical synthesis; Adrenergic beta-2 Receptor Agonists - chemistry; Adrenergic beta-2 Receptor Agonists - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Humans; Indans - chemical synthesis; Indans - chemistry; Indans - pharmacology; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacology; Receptors, Adrenergic, beta-2 - metabolism; Science & Technology; Structure-Activity Relationship; Binding kinetics; ANALOGS; Bronchodilator; RECEPTOR; ASTHMA; Indacaterol; BETA ADRENOCEPTOR; beta-Adrenoceptor agonists; DURATION; COPD
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.07.096

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 beta(2)-adrenoceptor identified the 3,4-dihydroquinolinone and 5-n-butylindanyl analogues to demonstrate the most similar profiles to indacaterol. An alpha-methyl aminoindane analogue was discovered to be 25-fold more potent than indacaterol, and functional studies revealed an atypical beta(2)-adrenoceptor activation profile for this compound consistent with that of a slowly dissociating 'super agonist'. (C) 2012 Elsevier Ltd. All rights reserved.