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

  • Bioorg Med Chem Lett. 2012 Oct 1;22(19):6280-5. doi: 10.1016/j.bmcl.2012.07.096.
David Beattie  1 ,  David Beer ,  Michelle E Bradley ,  Ian Bruce ,  Steven J Charlton ,  Bernard M Cuenoud ,  Robin A Fairhurst ,  David Farr ,  John R Fozard ,  Diana Janus ,  Elizabeth M Rosethorne ,  David A Sandham ,  David A Sykes ,  Alexandre Trifilieff ,  Katharine L Turner ,  Elke Wissler
Affiliations
  • 1. Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom.
PMID: 22932315 DOI: 10.1016/j.bmcl.2012.07.096
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'.