An investigation into the structure-activity relationships associated with the systematic modification of the β2-adrenoceptor agonist indacaterol

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 β2-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 β2-adrenoceptor activation profile for this compound consistent with that of a slowly dissociating 'super agonist'.