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

作者：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

来源：Bioorganic & Medicinal Chemistry Letters, 2012, 22(19): 6280-6285.

DOI：10.1016/j.bmcl.2012.07.096

• beta(2)-Adrenoceptor agonists
• COPD
• Indacaterol
• Binding kinetics
• Bronchodilator

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'.

• 出版日期2012-10-1