The Design of the Indacaterol Molecule

β2-Adrenoceptor agonists have been used as bronchodilators for the treatment of asthma and COPD for over a century. Throughout this period, β2-adrenoceptor agonists have continued to evolve to best meet the needs of the patient, with improvements having been made to the selectivity, route of administration and duration of effect. As the next step in the progression of this class of compound, ultra-long-acting inhaled β2-adrenoceptor agonists, suitable for once-daily dosing, have been targeted to provide a new gold standard in patient compliance. Indacaterol is the first of these agents to be approved for the treatment of COPD, having been designed by a rationale approach to deliver the optimal ultra-long-acting inhaled β2-adrenoceptor agonist profile. Indacaterol was designed following a lipophilicity-based hypothesis to maximise the retention of the compound in the airways, so as to be able to deliver the primary goal of 24 h bronchodilation following a single inhaled dose. Further evaluation then ensured the long duration of effect could be combined with the best overall profile with respect to potency, selectivity, onset of action and side-effect profile. Following the synthesis of a series of close analogues, in which all three regions of the pharmacophore were modified, indacaterol could be confirmed as the optimal compound from the series. Studies to better understand the mechanisms by which indacaterol achieves the observed pharmacological profile are discussed.